Long acting β-2-agonists and their use as medicaments

ABSTRACT

The present invention relates to compounds of formula 1 
                         
wherein the groups X, R a , R b , R 1 , R 1′ , R 2 , R 2′ , R 2″ , R 2′″ , V and n may have the meanings given in the claims and in the specification, and the use thereof as pharmaceutical compositions, particularly for the treatment of inflammatory and obstructive respiratory complaints.

RELATED APPLICATIONS

Benefit of U.S. Provisional Application Ser No. 60/557,081, filed onMar. 26, 2004, is hereby claimed, and which application is incorporatedherein in its entirety.

FIELD OF THE INVENTION

The present invention relates to compounds of formula 1

wherein the groups X, R^(a), R^(b), R¹, R^(1′), R², R^(2′), R^(2″),R^(2′″), V and n may have the meanings given in the claims and in thespecification, processes for preparing them and their use aspharmaceutical compositions, particularly for the treatment ofinflammatory and obstructive respiratory complaints.

BACKGROUND OF THE INVENTION

Betamimetics (β-adrenergic substances) are known from the prior art. Inthis respect reference is made for example to the disclosure of EP 43940 or WO 01/83462, which propose betamimetics for the treatment of awide range of diseases.

For the drug treatment of diseases it is often desirable to preparemedicaments with a longer duration of activity. As a rule, this ensuresthat the concentration of the active substance in the body needed toachieve the therapeutic effect is guaranteed for a longer period withoutthe need to re-administer the drug at frequent intervals. Moreover,giving an active substance at longer time intervals contributes to thewellbeing of the patient to a high degree.

It is particularly desirable to prepare a pharmaceutical compositionwhich can be used therapeutically by administration once a day (singledose). The use of a drug once a day has the advantage that the patientcan become accustomed relatively quickly to regularly taking the drug atcertain times of the day.

The aim of the present invention is therefore to provide betamimeticswhich are characterised by a longer duration of activity and can thus beused to prepare pharmaceutical compositions with a longer duration ofactivity. A particular aim of the invention is to prepare betamimeticswhich, by virtue of their long-lasting effect, can be used to prepare adrug for administration once a day. A further objective of the inventionis to prepare new betamimetics which, by virtue of their long-lastingeffect, can be used to prepare a drug for administration once a day forthe treatment of inflammatory or obstructive respiratory complaints.

In addition to the above objectives, the present invention also sets outto provide betamimetics which are not only exceptionally potent but arealso characterised by a high degree of selectivity with respect to theβ₂-adreno-receptor.

DETAILED DESCRIPTION OF THE INVENTION

Surprisingly it has been found that the above-mentioned objectives areachieved by compounds of general formula 1.

Accordingly, the present invention relates to compounds of generalformula 1

wherein

-   X denotes a group —O, —NH, —CH₂—O, —CHMe-O, —C(Me)₂-O, —CH₂—NH,    —CHMe-NH, —C(Me)₂-NH, —CH═CH— or —CH₂—CH₂—;-   V denotes a double-bonded group selected from among CH₂, NH and O,    preferably CH₂ and O, particularly preferably O;-   R^(a) and R^(b) which may be identical or different, denote a group    selected from among hydrogen, C₁₋₄-alkyl, and halogen-C₁₋₄-alkyl, or-   R^(a) and R^(b) together denote a C₂₋₅-alkylene-bridge, wherein one    or more hydrogen atoms may optionally be replaced by halogen;-   R¹ and R^(1′) which may be identical or different, denote a group    selected from among hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    halogen-C₁₋₆-alkyl, halogen-C₃₋₆-cycloalkyl or    C₁₋₆-alkylene-C₃₋₆-cycloalkyl, or-   R¹ and R^(1′) together denote a C₂₋₅-alkylene-bridge wherein one or    more hydrogen atoms may optionally be replaced by halogen;-   R², R^(2′), R^(2″) and R^(2′″) which may be identical or different,    denote a group selected from among hydrogen, C₁₋₆-alkyl,    halogen-C₁₋₆-alkylene, OH, HO—C₁₋₆-alkylene, —O—C₁₋₆-alkyl,    C₆₋₁₀-aryl, C₆₋₁₀-aryl-C₁₋₄-alkylene, C₆₋₁₀-aryl-C₁₋₆-alkylene-O,    COOH, COOC₁₋₆-alkyl, O—C₁₋₆-alkylene-COOH,    O—C₁₋₆-alkylene-COOC₁₋₆-alkyl, NHSO₂—C₁₋₆-alkyl, CN, NH₂,    NH—C₁₋₆-alkyl, N(C₁₋₆-alkyl)₂, NO₂, S—C₁₋₆-alkyl, SO₂—C₁₋₆-alkyl,    SO—C₁₋₆-alkyl, O(CO)C₁₋₆-alkyl, COC₁₋₆-alkyl, NHCOC₁₋₆-alkyl or    halogen;-   n denotes 0, 1 or 2; preferably 1;    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Preferred are the compounds of formula 1 wherein

-   X denotes —O, —CH₂—O, —C(Me)₂-O— or —CH═CH—;-   V denotes a double-bonded group selected from the group consisting    of CH₂, NH and O,preferably CH₂ and O, particularly preferably O;-   R^(a)and R^(b) which may be identical or different, denote a group    selected from among hydrogen, C₁₋₄-alkyl and fluoro-C₁₋₄-alkyl, or-   R^(a)and R^(b) together denote a group selected from —CH₂—CH₂,    —CH₂—CH₂—CH₂—CH₂— and —CH₂—CH₂—CH₂—CH₂—CH₂, wherein one or more    hydrogen atoms may optionally be replaced by fluorine or chlorine,    preferably fluorine;-   R¹ and R^(1′) which may be identical or different, denote a group    selected from among hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    halogen-C₁₋₆-alkyl or C₁₋₆-alkylene-C₃₋₆-cycloalkyl, or-   R¹ and R^(1′) together denote a group selected from —CH₂—CH₂,    —CH₂—CH₂—CH₂—CH₂— and —CH₂—CH₂—CH₂—CH₂—CH₂, wherein one or more    hydrogen atoms may optionally be replaced by fluorine or chlorine,    preferably fluorine;-   R², R^(2′), R^(2″) and R^(2′″) which may be identical or different,    denote a group selected from among hydrogen, C₁₋₄-alkyl, CF₃, CHF₂,    CH₂F, OH, —O—C₁₋₄-alkyl, phenyl, phenylethyl, benzyl, phenyloxy,    benzyloxy, COOH, COOC₁₋₄-alkyl, COCH₂COOH, OCH₂COOC₁₋₄-alkyl,    NHSO₂—C₁₋₄-alkyl, fluorine, chlorine or bromine;-   n denotes 0, 1 or 2; preferably 1;    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Particularly preferred are the compounds of formula 1 wherein

-   X denotes —O, —CH₂—O, —C(Me)₂-O— or —CH═CH—;-   V denotes a double-bonded group selected from among CH₂ and O,    preferably O;-   R^(a) and R^(b) which may be identical or different, denote a group    selected from among hydrogen, methyl, ethyl and CF₃, preferably    hydrogen, methyl or ethyl, or-   R^(a) and R^(b) together denote a group selected from —CH₂—CH₂— and    —CH₂—CH₂—CH₂—CH₂, preferably —CH₂—CH₂—;-   R¹ and R^(1′) which may be identical or different, denote a group    selected from among hydrogen, methyl, ethyl, propyl, cyclopropyl or    methylcyclopropyl, or-   R¹ and R^(1′) together denote —CH₂—CH₂—CH₂—CH₂— or    —CH₂—CH₂—CH₂—CH₂—CH₂—;-   R², R², R^(2″) and R^(2′″) which may be identical or different,    denote a group selected from among hydrogen, methyl, ethyl, propyl,    CF₃, CHF₂, CH₂F, OH, methyloxy, ethyloxy, propyloxy, COOH, COOCH₃,    COOCH₂CH₃, OCH₂COOH, OCH₂COOCH₃, NHSO₂—CH₃, fluorine, chlorine or    bromine;-   n denotes 0, 1 or 2; preferably 1,    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Of particular importance according to the invention are the compounds offormula 1 wherein R^(a) and R^(b) both represent methyl and wherein thegroups X, R¹, R^(1′), R², R^(2′), R^(2″), R^(2′″), V and n may have theabove-mentioned meanings. These preferred compounds may be representedby the following general formula 1.1

wherein the groups X, R¹, R^(1′), R², R^(2′), R^(2″), R^(2′″), V and nmay have the above-mentioned meanings.

Of particular importance according to the invention are the compounds offormula 1 wherein X corresponds to the group —CH₂—O—. These compoundsmay be represented by the formula 1′

wherein the groups R^(a), R^(b), R¹, R^(1′), R², R^(2′), R^(2″), R^(2′″)and V are as hereinbefore defined.

Preferred compounds are those of formula 1′, wherein R^(a) and R^(b) mayhave the above-mentioned meanings and wherein

-   V denotes a double-bonded group selected from the group consisting    of CH₂ and O, preferably O;-   R¹ and R^(1′) which may be identical or different, denote a group    selected from among hydrogen, methyl, ethyl, propyl or cyclopropyl,    or-   R¹ and R^(1′) together denote —CH₂—CH₂—CH₂—CH₂— or    —CH₂—CH₂—CH₂—CH₂—CH₂—;-   R² and R^(2′″) denote hydrogen;-   R^(2′) and R^(2″) which may be identical or different, denote a    group selected from among hydrogen, methyl, CF₃, OH, methyloxy,    benzyloxy, COOH, COOCH₃ or fluorine;-   n denotes 0, 1 or 2, preferably 1;    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Preferred compounds of formula 1′ according to the invention are thosewherein R^(a) and R^(b) may have the above-mentioned meanings andwherein

-   V denotes a double-bonded group selected from among CH₂ and O,    preferably O;-   R¹ and R^(1′) which may be identical or different denote hydrogen,    methyl, ethyl, propyl or cyclopropyl, or-   R¹ and R^(1′) together denote —CH₂—CH₂—CH₂—CH₂—CH₂—;-   R² and R^(2′) denote hydrogen;-   R^(2′) and R^(2″) which may be identical or different, denote a    group selected from among hydrogen, methyl, CF₃, OH, methyloxy,    benzyloxy or fluorine;-   n denotes 0, 1 or 2, preferably 1;    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Of equal importance according to the invention are the compounds offormula 1′, wherein R^(a) and R^(b) may have the above-mentionedmeanings and wherein

-   V denotes the double-bonded group O;-   R¹ and R^(1′) which may be identical or different, preferably    identical, denote hydrogen, methyl, ethyl or propyl;-   R², R^(2′) and R^(2″) denote hydrogen;-   R^(2′) denotes hydrogen, OH, methyloxy or benzyloxy,-   n denotes 0, 1 or 2, preferably 1;    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Also of exceptional importance according to the invention are thecompounds of formula 1′ wherein R^(a) and R^(b) may have theabove-mentioned meanings and wherein

-   V denotes the double-bonded group O;-   R¹ and R^(1′) in each case simultaneously denote hydrogen, methyl,    ethyl or propyl;-   R², R^(2′) and R^(2′″) denote hydrogen;-   R^(2′) denotes hydrogen, OH or methyloxy,-   n denotes 0, 1 or 2, preferably 1;    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Also of particular importance according to the invention are thosecompounds of formula 1′wherein R^(a) and R^(b) both represent methyl.These compounds may be represented by formula 1.1′

wherein the groups R¹, R^(1′), R², R^(2′), R^(2″), R^(2′″) and V mayhave the above-mentioned meanings.

Preferred compounds of formula 1 are those wherein X corresponds to thegroup —O—. These compounds may be represented by the formula 1″

wherein the groups R^(a), R^(b), R¹, R^(1′), R², R^(2′), R^(2″), R^(2′″)and V have the above-mentioned meanings.

Particularly preferred are compounds of formula 1″, wherein R^(a) andR^(b) may have the above-mentioned meanings and wherein

-   V denotes a double-bonded group selected from among CH₂ and O,    preferably O;-   R¹ and R^(1′) which may be identical or different denote a group    selected from among hydrogen, methyl, ethyl, propyl, cyclopropyl, or-   R¹ and R^(1′) together denote —CH₂—CH₂—CH₂—CH₂— or    —CH₂—CH₂—CH₂—CH₂—CH₂—;-   R² and R^(2′″) denote hydrogen;-   R^(2′) and R^(2″) which may be identical or different denote a group    selected from among hydrogen, methyl, CF₃, OH, methyloxy, benzyloxy,    COOH, COOCH₃ or fluorine;-   n denotes 0, 1 or 2, preferably 1;    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Also particularly preferred are compounds of formula 1″, wherein R^(a)and R^(b) may have the above-mentioned meanings and wherein

-   V denotes a double-bonded group selected from among CH₂ and O,    preferably O;-   R¹ and R^(1′) which may be identical or different denote hydrogen    methyl, ethyl or propyl, or-   R¹ and R^(1′) together denote —CH₂—CH₂—CH₂—CH₂—CH₂—;-   R² and R^(2′″) denote hydrogen;-   R^(2′) and R^(2″) which may be identical or different denote a group    selected from among hydrogen, methyl, CF₃, OH, methyloxy, benzyloxy    or fluorine;-   n denotes 0, 1 or 2, preferably 1;    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Also of equal importance according to the invention are the compounds offormula 1″, wherein R^(a) and R^(b) may have the above-mentionedmeanings and wherein

-   V denotes the double-bonded group O;-   R¹ and R^(1′) which may be identical or different, preferably    identical, denote hydrogen, methyl or ethyl;-   R², R^(2″) and R^(2″) denote hydrogen;-   R^(2′) denotes hydrogen, OH, methyloxy or benzyloxy,-   n denotes 0, 1 or 2, preferably 1;    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Also of particular importance according to the invention are thosecompounds of formula 1″ wherein R^(a) and R^(b) both represent methyl.These compounds may be represented by the formula 1.1″

wherein the groups R¹, R^(1′), R², R^(2′), R^(2″), R^(′″) and V may havethe above-mentioned meanings.

Also of particular importance according to the invention are compoundsof formula 1 wherein X corresponds to the group —CH═CH—. These compoundsmay be represented by the formula 1′″

wherein the groups R^(a), R^(b), R¹, R^(1′), R², R^(2′), R^(2″), R^(2′″)and V are as hereinbefore defined.

Preferred are compounds of formula 1′″ wherein R^(a) and R^(b) may havethe above-mentioned meanings and wherein

-   V denotes a double-bonded group selected from among CH₂ and O,    preferably O;-   R¹ and R^(1′) which may be identical or different denote a group    selected from among hydrogen, methyl, ethyl, propyl, cyclopropyl,    preferably methyl or ethyl, or-   R¹ and R^(1′) together denote —CH₂—CH₂, —CH₂—CH₂—CH₂—CH₂— or    —CH₂—CH₂—CH₂—CH₂—CH₂—;-   R² and R^(2′″) denote hydrogen;-   R^(2′) and R^(2″) which may be identical or different denote a group    selected from among hydrogen, methyl, CF₃, OH, methyloxy, benzyloxy,    COOH, COOCH₃ or fluorine;-   n denotes 0, 1 or 2, preferably 1;    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Particularly preferred are compounds of formula 1′″, wherein R^(a) andR^(b) may have the above-mentioned meanings and wherein

-   V denotes a double-bonded group selected from the group consisting    from CH₂ and O, preferably O;-   R¹ and R^(1′) which may be identical or different denote hydrogen    methyl, ethyl or propyl, or-   R¹ and R^(1′) together denote —CH₂—CH₂, —CH₂—CH₂—CH₂—CH₂— or    —CH₂—CH₂—CH₂—CH₂—CH₂—;-   R² and R^(2′″) denote hydrogen;-   R^(2′) and R^(2″) which may be identical or different denote a group    selected from among hydrogen, methyl, CF₃, OH, methyloxy, benzyloxy    or fluorine;-   n denotes 0, 1 or 2, preferably 1;    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Also particularly preferred are compounds of formula 1′″ wherein R¹ andR^(b) may have the above-mentioned meanings and wherein

-   V denotes the double-bonded group O;-   R¹ and R^(1′) which may be identical or different, preferably    identical, denote hydrogen, methyl, ethyl or propyl;-   R², R^(2″) and R^(2″) denote hydrogen;-   R^(2′) denotes hydrogen, OH, methyloxy or benzyloxy,-   n denotes 0, 1 or 2, preferably 1;    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Also of exceptional importance according to the invention are thecompounds of formula 1′″, wherein R^(a) and R^(b) may have theabove-mentioned meanings and wherein

-   V denotes the double-bonded group O;-   R¹ and R^(1′) in each case simultaneously denote hydrogen, methyl,    ethyl or propyl;-   R², R^(2″) and R^(2′″) denote hydrogen;-   R^(2′) denotes hydrogen, OH or methyloxy,-   n denotes 0, 1 or 2, preferably 1;    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Also of particular importance according to the invention are thosecompounds of formula 1′″ wherein R^(a) and R^(b) both represent methyl.These compounds may be represented by the formula 1.1′″

wherein the groups R¹, R^(1′), R², R^(2′), R^(2″), R^(2′″) and V mayhave the above-mentioned meanings.

Also of particular importance according to the invention are compoundsof formula 1 wherein X denotes the group —CMe₂-O—. These compounds maybe represented by the formula 1″″

wherein the groups R^(a), R^(b), R¹, R^(1′), R², R^(2′), R^(2″), R^(2′″)and V are as hereinbefore defined.

Preferred are compounds of formula 1″″ wherein R^(a) and R^(b) may havethe above-mentioned meanings and wherein

-   V denotes a double-bonded group selected from among CH₂ and O,    preferably O;-   R¹ and R^(1′) which may be identical or different, denote a group    selected from among hydrogen, methyl, ethyl, propyl, cyclopropyl, or-   R¹ and R^(1′) together denote —CH₂—CH₂—CH₂—CH₂— or    —CH₂—CH₂—CH₂—CH₂—CH₂—;-   R² and R^(2′″) denote hydrogen;-   R^(2′) and R^(2″) which may be identical or different, denote a    group selected from among hydrogen, methyl, CF₃, OH, methyloxy,    benzyloxy, COOH, COOCH₃ or fluorine;-   n denotes 0, 1 or 2, preferably 1;    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Particularly preferred are compounds of formula 1″″ wherein R^(a) andR^(b) may have the above-mentioned meanings and wherein

-   V denotes a double-bonded group selected from among CH₂ and O,    preferably O;-   R¹ and R^(1′) which may be identical or different, denote hydrogen,    methyl, ethyl or propyl or-   R¹ and R^(1′) together denote —CH₂—CH₂—CH₂—CH₂—CH₂—;-   R² and R^(2′″) denote hydrogen;-   R² and R^(2″) which may be identical or different, denote a group    selected from among hydrogen, methyl, CF₃, OH, methyloxy, benzyloxy    or fluorine;-   n denotes 0, 1 or 2, preferably 1;    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Also particularly preferred are the compounds of formula 1″″ whereinR^(a) and R^(b) may have the above-mentioned meanings and wherein

-   V denotes the double-bonded group O;-   R¹ and R^(1′) which may be identical or different, preferably    identical, denote hydrogen, methyl, ethyl or propyl;-   R², R^(2″) and R^(2″) denote hydrogen;-   R^(2′) denotes hydrogen, OH, methyloxy or benzyloxy,-   n denotes 0, 1 or 2, preferably 1;    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Also of exceptional importance according to the invention are thecompounds of formula 1″″, wherein R^(a) and R^(b) may have theabove-mentioned meanings and wherein

-   V denotes the double-bonded group O;-   R¹ and R^(1′) in each case simultaneously denote hydrogen, methyl,    ethyl or propyl;-   R², R^(2″) and R^(2′″) denote hydrogen;-   R^(2′) denotes hydrogen, OH or methyloxy,-   n denotes 0, 1 or 2, preferably 1;    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Also of particular importance according to the invention are thosecompounds of formula 1″″ wherein R^(a) and R^(b) both represent methyl.These compounds may be represented by the formula 1.1″″

wherein the groups R¹, R^(1′), R², R^(2′), R^(2″), R^(2′″) and V mayhave the above-mentioned meanings.

Also of outstanding importance according to the invention are thecompounds of formula 1 wherein

-   R¹ and R^(1′) in each case simultaneously denote hydrogen, methyl or    ethyl, preferably methyl or ethyl, particularly preferably ethyl;    and the groups X, R², R^(2′), R^(2″), R^(2′″), V and n may have one    of the above-mentioned meanings, optionally in the form of the    individual optical isomers, mixtures of the individual enantiomers    or racemates, in the form of the free bases or the corresponding    acid addition salts with pharmacologically acceptable acids.

Also of exceptional importance according to the invention are thecompounds of formula 1, wherein

-   n 1    and the groups X, R¹, R^(1′), R², R^(2′), R^(2″), R^(2′″) and V may    have one of the above-mentioned meanings, optionally in the form of    the individual optical isomers, mixtures of the individual    enantiomers or racemates, in the form of the free bases or the    corresponding acid addition salts with pharmacologically acceptable    acids.

Particularly preferred compounds of general formula 1 are selected fromamong:

-   -   1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8)-yl-ethylamino]-3-methyl-butyl}-6-methoxy-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one,    -   6-hydroxy-1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one,

-   4,4-diethyl-1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one,    -   6-hydroxy-8-{1-hydroxy-2-[3-(3-hydroxy-4,4-dimethyl-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-1,1        -dimethyl-propylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,    -   1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-1,4-dihydro-benzo[1,3]oxazin-2-one,

-   4-ethyl-1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-1,4-dihydro-benzo[1,3]oxazin-2-one,    -   8-{2-[1,1        -dimethyl-3-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,    -   4,4-diethyl-1-{3-[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydro-quinolin-5-yl)-ethylamino]-3-methyl-butyl}-1,4-dihydro-benzo[1,3]oxazin-2-one,    -   4,4-diethyl-1-{3        -[2-hydroxy-2-(6-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one,    -   4,4-diethyl-1-{3-[2-hydroxy-2-(6-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one,    -   4,4-diethyl-1-{3-[2-hydroxy-2-(7-hydroxy-2-oxo-1,2-dihydro-quinolin-5-yl)-ethylamino]-3-methyl-butyl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one,    -   1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-4,4-dipropyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one,    -   1-{3-[2-hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-4,4-dipropyl-1,4-dihydro-benzo[d][1,3        ]oxazin-2-one,    -   4,4-diethyl-7-fluoro-1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one,    -   4,4-diethyl-1-{3-[2-hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one,    -   1-(2-{1-[2-hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-cyclopropyl}-ethyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one,    -   1-(2-{1-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-cyclopropyl}-ethyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one,    -   1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-spiro(cyclohexane-1,4′-2H-3′,        1′-benzoxazin)-2′-one,    -   1-{3-[2-hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-spiro(cyclohexane-1,4′-2H-3′,1′-benzoxazin)-2′-one;    -   4,4-dimethyl-1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-propyl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one;    -   4,4-dimethyl-1-{3-[2-hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-propyl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one,        optionally in the form of the individual optical isomers,        mixtures of the individual enantiomers or racemates, in the form        of the free bases or the corresponding acid addition salts with        pharmacologically acceptable acids

The OH— group may be configured in three different positions in thecompounds of formula 1 defined hereinbefore. The preferred isomers maybe represented by the following general formulae 1a and 1b,

wherein the groups X, R^(a), R^(b), R¹, R^(1′), R², R^(2′), R^(2″),R^(2′″), V and n may have the above-mentioned meanings.

Particularly preferred compounds are particularly also those of generalformula 1.1′-b

wherein the groups R¹, R^(1′), R², R^(2′), R^(2″), R^(2′″) and V mayhave the above-mentioned meanings.

Particularly preferred compounds are particularly also those of generalformula 1.1″-b

wherein the groups R¹, R^(1′), R², R^(2′), R^(2″), R^(2′″) and V mayhave the above-mentioned meanings.

Particularly preferred compounds are particularly also those of generalformula 1.1′″-a

wherein the groups R¹, R^(1′), R², R^(2′), R^(2″), R^(2′″) and V mayhave the above-mentioned meanings.

Particularly preferred compounds are particularly also those of generalformula 1.1″″-b

wherein the groups R¹, R^(1′), R², R^(2′), R^(2″), R^(2′″) and V mayhave the above-mentioned meanings.

The compounds of formula 1 may optionally be used in the form of theindividual optical isomers, mixtures of the individual enantiomers orracemates. They are particularly preferably used in the form of theenantiomerically pure compounds, while the compounds of formula 1wherein the asymmetric carbon centre “—CH(OH)—” benzylic to the phenylring is in the R configuration [sic]. The particularly preferredR-enantiomers of the compounds of general formula 1 may be representedby general formula R-1,

wherein the groups X, R^(a), R^(b), R¹, R^(1′), R², R^(2′), R^(2″),R^(2′″), V and n may have the above-mentioned meanings.

By acid addition salts with pharmacologically acceptable acids aremeant, for example, the salts selected from among the hydrochloride,hydrobromide, hydroiodide, hydrosulphate, hydrophosphate,hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate,hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate, preferablythe hydrochloride, hydrobromide, hydrosulphate, hydrophosphate,hydrofumarate and hydromethanesulphonate.

Halogen within the scope of the present invention denotes fluorine,chlorine, bromine or iodine. Unless stated otherwise, fluorine andbromine are the preferred halogens, while fluorine is generallypreferred.

Unless otherwise stated, the alkyl groups (alkyl) are straight-chainedor branched alkyl groups having 1 to 6, preferably 1 to 4 carbon atoms.The following are mentioned by way of example: methyl, ethyl, propyl orbutyl. In some cases the abbreviations Me, Et, Prop or Bu are used todenote the groups methyl, ethyl, propyl or butyl. Unless otherwisestated, the definitions propyl and butyl include all the possibleisomeric forms of the groups in question. Thus, for example, propylincludes n-propyl and iso-propyl, butyl includes iso-butyl, sec.butyland tert.-butyl, etc.

Examples of alkylene groups (alkylene), unless otherwise stated, arebranched and unbranched alkylene groups with 1 to 6, preferably 1 to 4carbon atoms. The following are mentioned by way of example: methylene,ethylene, propylene or butylene. Unless stated otherwise, thedefinitions propylene and butylene include all the possible isomericforms of the groups in question.

Examples of cycloalkyl groups (cycloalkyl), unless otherwise stated, arecyclic alkyl groups with 3 to 6. The following are mentioned by way ofexample: cyclopropyl, cyclobutanyl, cyclopentyl or cyclohexyl.

Examples of alkyloxy groups (O-alkyl), unless otherwise stated, arebranched and unbranched alkyl groups with 1 to 6, preferably 1 to 4carbon atoms, linked via an oxygen atom. The following are mentioned byway of example: methyloxy, ethyloxy, propyloxy or butyloxy. In somecases the abbreviations —OMe, —OEt, —Oprop or —OBu are used to denotethe groups methyloxy, ethyloxy, propyloxy or butyloxy. Unless statedotherwise, the definitions propyloxy and butyloxy include all thepossible isomeric forms of the groups in question. Thus, for example,propyloxy includes n-propyloxy and iso-propyloxy, butyloxy includesiso-butyloxy, sec-butyloxy and tert-butyloxy etc. In some cases withinthe scope of the present invention the term alkoxy may be used insteadof the term alkyloxy. The groups methyloxy, ethyloxy, propyloxy or alsobutyloxy may optionally also be referred to as methoxy, ethoxy, propoxyor butoxy.

Examples of halogenoalkylene groups, unless otherwise stated, arebranched and unbranched alkyl groups with 1 to 6 carbon atoms, whereinone or more hydrogen atoms are replaced by halogen atoms, preferably byfluorine. The following are mentioned, for example: CHF₂, CF₃, CH₂CF₃,CF₂CF₃.

Suitable aryl groups, unless otherwise stated, are aromatic ring systemswith 6 to 10 carbon atoms. Preferred aryl groups are phenyl andnaphthyl, while phenyl is particularly preferred according to theinvention.

The term arylalkylene groups, unless otherwise stated, refers to theabove-mentioned aryl groups which are linked via branched and unbranchedalkyl groups with 1 to 4 carbon atoms. Examples include benzyl,phenylethyl, naphthylmethyl, naphthylethyl. The bridging alkyl groupsare also referred to, within the scope of the present invention, asalkylene bridges.

The term aryloxy groups (O-aryl), unless otherwise stated, refers toaryl groups with 6 to 10 carbon atoms which are linked via an oxygenbridge. Preferred groups in this context include for example phenyloxyor naphthyloxy, which may optionally also be referred to as phenoxy ornaphthoxy within the scope of the present invention.

The term arylalkylenoxy groups (arylalkylene-O—), unless otherwisestated, refers to aryl groups which are linked via branched andunbranched alkyloxy groups with 1 to 4 carbon atoms. Examples includebenzyloxy, phenylethyloxy, naphthylmethyloxy, naphthylethyloxy.

The compounds according to the invention may be prepared analogously tomethods already known in the art. Suitable methods of preparation areknown for example from EP 43 940 or from WO 01/83462, to which referenceis hereby made in its entirety.

The examples of synthesis described below serve to illustrate newcompounds according to the invention in more detail. However, they areintended only as examples of procedures to illustrate the inventionwithout restricting it to the subject matter described in anexemplifying capacity hereinafter.

EXAMPLE 11-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-6-methoxy-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

a) ethyl (2-acetyl-4-methoxy-phenyl)-carbamate

65.1 g (0.6 mol) ethyl chloroformate are added dropwise to a solution of82.5 g (0.5 mol) 2-amino-5-methoxyacetophenone in 400 mL pyridine whilecooling, so that the temperature does not exceed 10–15° C. Then thereaction mixture is stirred for 2 h at ambient temperature and thenpoured onto ice. The precipitate formed is suction filtered, washed withwater and recrystallised from isopropanol.

Yield: 102 g (86%); m.p.=97–100° C.

b) 6-methoxy-4,4-dimethyl-1,4-dihydro-benzo[1,3]oxazin-2-one

47.4 g (0.2 mol) ethyl (2-acetyl-4-methoxy-phenyl)-carbamate, dissolvedin 275 mL THF, are added dropwise to a solution of 0.5 molmethylmagnesium iodide in 200 mL diethyl ether while cooling so that thetemperature does not exceed 0° C. The mixture is stirred for 30 minutesat ambient temperature and then for 2 hours at reflux temperature. Thereaction mixture is poured onto ice and combined with ammonium chloride.After the organic phase has been separated off it is repeatedlyextracted with ethyl acetate. The organic phases are combined, washedwith water, dried with sodium sulphate and evaporated down. The residueis dissolved in methanol and the solution is evaporated down and thencombined with water. The precipitate formed is separated off, washedwith water and recrystallised from toluene. Yield: 31.1 g (75%);m.p.=178–180° C.

c)1-(3-amino-3-methyl-butyl)-6-methoxy-4,4-dimethyl-1,4-dihydro-benzo[1,3]oxazin-2-one

A solution of 31 g (0.15 mol)6-methoxy-4,4-dimethyl-1,4-dihydro-benzo[1,3]oxazin-2-on in 120 mL HMPTis added dropwise at 65–70° C. to 7.2 g sodium hydride (55–60%) in 30 mLHMPT. After the release of hydrogen has ended the mixture is stirred foranother 20 minutes and then cooled to ambient temperature. At thistemperature 37.7 g (0.18 mol)(3-chloro-1,1-dimethyl-propyl)-benzylideneamine, dissolved in 40 mLHMPT, are added. After 3 hours stirring at 100° C. the reaction mixtureis poured onto ice poured and extracted with ethyl acetate. The organicphases are washed with water, dried with sodium sulphate and evaporateddown. The residue is dissolved in 1 N hydrochloric acid with heating andafter cooling extracted with diethyl ether. The aqueous phase is madealkaline with sodium hydroxide solution and extracted with ethylacetate. Then the organic phase is dried with sodium sulphate and freedfrom solvent. The product is isolated from the residue in the form ofits hydrochloride, after dissolving in acetonitrile and adding etherealhydrochloric acid. Yield: 34.3 g (70%).

d)1-{3-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxy-ethylamino]-3-methyl-butyl}-6-methoxy-4,4-dimethyl-1,4-dihydro-benzo[1,3]oxazin-2-one

357 mg (1 mmol) of6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and292 mg (1 mmol)1-(3-amino-3-methyl-butyl)-6-methoxy-4,4-dimethyl-1,4-dihydro-benzo[1,3]oxazin-2-oneare suspended in 5 mL ethanol and heated to 70° C. The solution obtainedis stirred for one hour at 70° C. and then cooled to ambienttemperature. After the addition of 113 mg (3 mmol) sodium borohydridethe mixture is stirred for 3 hours at ambient temperature, combined with0.7 mL saturated potassium carbonate solution and stirred for a further30 minutes. It is filtered through aluminium oxide (basic), washedrepeatedly with methylene chloride/methanol 15:1 and evaporated down.The crude product thus obtained is purified by chromatography (methylenechloride with methanol/ammonia gradient (9:1)). Beige solid. Yield: 340mg (58%); mass spectrometry: [M+H]⁺=590.

e)1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-6-methoxy-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

340 mg (0.58 mmol)1-{3-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxy-ethylamino]-3-methyl-butyl}-6-methoxy-4,4-dimethyl-1,4-dihydro-benzo[1,3]oxazin-2-oneare dissolved in 10 mL methanol and hydrogenated with palladium oncharcoal as catalyst at 1 bar hydrogen pressure. Then the catalyst isfiltered off and the filtrate is evaporated down. Beige solid. Yield:273 mg (95%); mass spectrometry: [M+H]⁺=500; Rf value=0.33 (methylenechloride:methanol:ammonia=9:1:0.1).

EXAMPLE 26-hydroxy-1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

a) 6-benzyloxy-4,4-dimethyl-1,4-dihydro-benzo[1,3]oxazin-2-one

Prepared analogously to the method described for Example 1b) from 15.7 g(50 mmol) ethyl (2-acetyl-4-benzyloxy-phenyl)-carbamate and 125 mmolmethylmagnesium iodide.

Yield: 10.8 g (76%); m.p.=134° C.

b)1-(3-amino-3-methyl-butyl)-6-benzyloxy-4,4-dimethyl-1,4-dihydro-benzo[1,3]oxazin-2-one

Prepared analogously to the method described for Example 1c) from 10.5 g(37 mmol) 6-benzyloxy-4,4-dimethyl-1,4-dihydro-benzo[1,3]oxazin-2-oneand 9.3 g (44 mmol) (3-chloro-1,1-dimethyl-propyl)-benzylideneamine.Yield: 10.9 g (73%); m.p.=233° C. (hydrochloride).

c)6-hydroxy-1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-4,4-dimethyl-1,4-dihydro-benzo[1,3]oxazin-2-one

The reaction of 357 mg (1 mmol)6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and368 mg (1 mmol)1-(3-amino-3-methyl-butyl)-6-benzyloxy-4,4-dimethyl-1,4-dihydro-benzo[1,3]oxazin-2-oneanalogously to the methods described for Example 1 yields the compoundin the form of a beige solid. Yield 355 mg (73%); mass spectrometry:[M+H]⁺=486.

EXAMPLE 34,4-diethyl-1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one

a) 4,4-diethyl-1,4-dihydro-benzo[1,3]oxazin-2-one

Obtained from the reaction of 67 g (0.3 mol) methyl2-ethoxycarbonylamino-benzoate and 1.14 mol ethylmagnesium iodideanalogously to the method described for Example 1b). Yield: 48.5 g(79%); m.p.=160–162° C.

b)1-(3-amino-3-methyl-butyl)-4,4-diethyl-1,4-dihydro-benzo[1,3]oxazin-2-one

Prepared from 47.5 g (0.23 mol)4,4-diethyl-1,4-dihydro-benzo[1,3]oxazin-2-one and 57.5 g (0.27 mol)(3-chloro-1,1-dimethyl-propyl)-benzylideneamine according to the methoddescribed for Example 1c). Yield: 38.1 g (50%); m.p.=208–210° C.(hydrochloride).

c)4,4-diethyl-1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one

357 mg (1 mmol)6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and290 mg (1 mmol)1-(3-amino-3-methyl-butyl)-4,4-diethyl-1,4-dihydro-benzo[1,3]oxazin-2-oneare reacted analogously to the methods described for Example 1. Aftersubsequent debenzylation a beige solid is obtained. Yield: 367 mg (74%);mass spectrometry: [M+H]⁺=498.

EXAMPLE 41-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

a) 4,4-dimethyl-1,4-dihydro-benzo[1,3]oxazin-2-one

112 g (1.13 mol) phosgene are piped into 500 mL THF. Then a solution of52 g (0.34 mol) 2-(2-amino-phenyl)-propan-2-ol, prepared from2-aminoacetophenone and methylmagnesium iodide, in 300 mL THF is added.The reaction mixture is left to stand overnight, evaporated down andcombined with 500 ml pyridine. After the pyridine has been distilled offwater is added and the mixture is extracted with diethyl ether. Theorganic phases are washed successively with 2 N hydrochloric acid,sodium hydroxide solution and water, dried with sodium sulphate andevaporated down. The residue remaining (46 g) is further reacteddirectly without any more purification.

m.p. (toluene/petroleum ether)=109–110° C.

b) 1-(3-amino-3-methyl-butyl)-4,4-dimethyl-1,4-dihydro-benzo[1,3]oxazin-2-one

Obtained from 43 g (0.24 mol)4,4-dimethyl-1,4-dihydro-benzo[1,3]oxazin-2-one and 54 g (0.26 mol)(3-chloro-1,1-dimethyl-propyl)-benzylideneamine analogously to themethod described for Example 1c). Yield 41 g (57%); m.p. (afterrecrystallisation from ethanol)=262° C. (hydrochloride).

c)1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

357 mg (1 mmol)6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and262 mg (1 mmol)1-(3-amino-3-methyl-butyl)-4,4-dimethyl-1,4-dihydro-benzo[1,3]oxazin-2-oneare reacted in the manner described for Example 1. After subsequenthydrogenation a beige solid is isolated. Yield: 285 mg (61%); massspectrometry [M+H]⁺=470.

EXAMPLE 51-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-1,4-dihydro-benzo[1,3]oxazin-2-one

a) 1-(3-amino-3-methyl-butyl)-1,4-dihydro-benzo[1,3]oxazin-2-one

2.70 g (18 mmol) 1,4-dihydro-benzo[1,3]oxazin-2-one and 4.35 g (21 mmol)(3-chloro-1,1-dimethyl-propyl)-(1-phenyl-methylidene)-amine are reactedin the manner described for Example 6a). For working up the reactionmixture is poured onto ice water and extracted with ethyl acetate. Theorganic phases are washed with water, dried with sodium sulphate andevaporated down. The residue is combined with 25 mL 2 N hydrochloricacid and heated to 70° C. After cooling to ambient temperature themixture is extracted with diethyl ether. The aqueous phase is evaporateddown and combined with acetonitrile. The precipitate formed is suctionfiltered and washed with acetonitrile and diethyl ether. Yield: 2.65 g(54%, hydrochloride); melting range: 220° C. (decomposition).

b)1-{3-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxy-ethylamino]-3-methyl-butyl}-1,4-dihydro-benzo[1,3]oxazin-2-one

357 mg (1 mmol)6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and234 mg (1 mmol)1-(3-amino-3-methyl-butyl)-1,4-dihydro-benzo[1,3]oxazin-2-one in 5 mLtetrahydrofuran are stirred for 15 minutes at 60° C. The mixture iscooled to 0° C. and 1.5 mL of a 2 molar solution of lithium borohydridein tetrahydrofuran are added dropwise under an argon atmosphere. Themixture is stirred for 15 min at 0° C., combined with 10 mLdichloromethane and 3 mL water, stirred for another hour and thenfiltered through kieselguhr. The mixture is eluted with dichloromethaneand the solvents are distilled off. The residue is purified bypreparative HPLC (reverse phase, acetonitrile/water gradient with 0.1%trifluoroacetic acid).

Yield: 196 mg (30%, trifluoroacetate); mass spectroscopy: [M]⁺=532.

c)1-{3-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxy-ethylamino]-3-methyl-butyl}-1,4-dihydro-benzo[1,3]oxazin-2-one

196 mg (0.3 mmol)1-{3-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxy-ethylamino]-3-methyl-butyl}-1,4-dihydro-benzo[1,3]oxazin-2-oneare dissolved in 5 ethanol and hydrogenated with palladium on charcoal(10%) as catalyst at 3 bar and ambient temperature. The catalyst isseparated off and the crude product is recrystallised fromacetonitrile/diethyl ether.

Yield: 48 mg (29%, trifluorethyl acetate); mass spectroscopy:[M+H]⁺=442.

EXAMPLE 64-ethyl-1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-1,4-dihydro-benzo[1,3]oxazin-2-one

a) 1-(3-amino-3-methyl-butyl)-4-ethyl-1,4-dihydro-benzo[1,4]oxazine

A solution of 17.7 g (0.10 mol)4-ethyl-1,4-dihydro-benzo[1,3]oxazin-2-one in 85 mL HMPT is combinedwith 4.8 g sodium hydride (55–60%) and slowly heated to 60° C. After thedevelopment of hydrogen has ended the mixture is stirred for another 30min at 80° C. and then cooled to ambient temperature. 25 g (0.12 mol)(3-chloro-1,1-dimethyl-propyl)-(1-phenyl-methylidene)-amine, dissolvedin 25 mL HMPT, are added and the mixture is stirred for three hours at100° C. The reaction mixture is cooled, poured onto ice water andextracted with ethyl acetate. The combined organic phases are washedwith water, dried with sodium sulphate and evaporated down. The residueis heated to 60° C. together with 240 mL 1N hydrochloric acid and aftercooling extracted with diethyl ether. The aqueous phase is made alkalinewith conc. sodium hydroxide solution and extracted with ethyl acetate.The combined organic phases are dried with sodium sulphate andevaporated down. The residue is dissolved in ethyl acetate with heating,combined with an equimolar amount of maleic acid and slowly cooled. Theprecipitate formed is suction filtered, washed with ethyl acetate anddried. Yield: 26.1 g (69%, maleate); melting range: 134° C.

b)1-{3-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxy-ethylamino]-3-methyl-butyl}-4-ethyl-1,4-dihydro-benzo[1,3]oxazin-2-one

357 mg (1 mmol)6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and530 mg (1 mmol)1-(3-amino-3-methyl-butyl)-4-ethyl-1,4-dihydro-benzo[1,4]oxazine arereacted and worked up analogously to the method described in 5b).

Yield: 308 mg (46%, trifluoroacetate); mass spectroscopy: [M]⁺=560.

c)4-ethyl-1-{1,3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-1,4-dihydro-benzo[1,3]oxazin-2-one

308 mg (0.46 mmol)1-{3-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxy-ethylamino]-3-methyl-butyl}-4-ethyl-1,4-dihydro-benzo[1,3]oxazin-2-oneare hydrogenated with palladium on charcoal (10%) as catalyst at ambienttemperature and under 3 bar hydrogen pressure. The catalyst is separatedoff, the filtrate evaporated down and the residue is chromatographed(reverse phase; acetonitrile/water gradient).

Yield: 14 mg (5%, trifluoroacetate); mass spectroscopy: [M]⁺=470.

EXAMPLE 78-{2-[1,1-dimethyl-3-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

a) 1-(3-amino-3-methyl-butyl)-3,4-dihydro-quinolin-2-one

Prepared analogously to the method described for Example 6a) from 15.7 g(107 mmol) 3,4-dihydro-quinolin-2-one and 24.9 g (119 mmol)(3-chloro-1,1-dimethyl-propyl)-(1-phenyl-methylidene)-amine. Unlike inthe method mentioned above the product is precipitated not as themaleate but as the hydrochloride.

Yield: 6.9 g (24%, hydrochloride); melting range: 200–203° C.

b)8-{2-[1,1-dimethyl-3-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

Prepared from 357 mg (1 mmol)6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and232 mg (1 mmol) 1-(3-amino-3-methyl-butyl)-3,4-dihydro-quinolin-2-oneanalogously to the method described for Example 5c). The finalpurification of the product is carried out by preparative HPLC (reversephase, acetonitrile/water gradient with 0.1% trifluoroacetic acid).

Yield: 94 mg (17%, trifluoroacetate); mass spectroscopy: [M]⁺=440.

EXAMPLE 84,4-diethyl-1-{3-[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydro-quinolin-5-yl)-ethylamino]-3-methyl-butyl}-1,4-dihydro-benzo[1,3]oxazin-2-one

a)1-{3-[2-(8-benzyloxy-2-oxo-1,2-dihydro-quinolin-5-yl)-2-hydroxy-ethylamino]-3-methyl-butyl}-4,4-diethyl-1,4-dihydro-benzo[1,3]oxazin-2-one

400 mg (1.4 mmol) of 8-benzyloxy-5-oxiranyl-quinolin-2-one and 436 mg(1.5 mmol)1-(3-amino-3-methyl-butyl)-4,4-diethyl-1,4-dihydro-benzo[1,3]oxazin-2-onein 5 mL of n-butanol are stirred for 6 hours at 140° C. The solvent isdistilled off and the residue is purified by chromatography (reversephase; acetonitrile/water gradient). Beige solid.

Yield: 160 mg (20%); mass spectroscopy: [M]⁺=584.

b)4,4-diethyl-1-{3-[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydro-quinolin-5-yl)-ethylamino]-3-methyl-butyl}-1,4-dihydro-benzo[1,3]oxazin-2-one

160 mg (0.3 mmol)1-{3-[2-(8-benzyloxy-2-oxo-1,2-dihydro-quinolin-5-yl)-2-hydroxy-ethylamino]-3-methyl-butyl}-4,4-diethyl-1,4-dihydro-benzo[1,3]oxazin-2-oneare dissolved in 5 mL methanol and hydrogenated in the presence ofpalladium on charcoal (10%). Yield: 49 mg (34%); mass spectroscopy:[M]⁺=494.

EXAMPLE 94,4-diethyl-1-{3-[2-hydroxy-2-(6-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-14-dihydro-benzo[d][1,3]oxazin-2-one

a)N-(3-acetyl-5-benzyloxy-2-hydroxy-3phenyl)-2-bromo-2-methyl-propionamide

4.64 g (25 mmol) 2-bromo-2-methyl-propionyl chloride are added dropwiseto a solution of 5.15 g (20 mmol)1-(3-amino-5-benzyloxy-2-hydroxy-phenyl)-ethanone in 20 mL pyridine at5–20° C. After the addition has ended the mixture is stirred for 15minutes, combined with ice water and 100 mL ethyl acetate and acidifiedwith conc. hydrochloric acid. The organic phase is separated off, washedwith water and dried with sodium sulphate. After the solvent has beendistilled off the residue is crystallised from a diethyl ether/petroleumether mixture. Yield: 6.8 g (84%); melting range: 88–90° C.

b) 8-acetyl-6-benzyloxy-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one

6.60 g (16.2 mmol)N-(3-acetyl-5-benzyloxy-2-hydroxy-phenyl)-2-bromo-2-methyl-propionamideand 2.76 g (20 mmol) potassium carbonate are stirred for 1 hour in 70 mLacetonitrile at reflux temperature. The solid is suction filtered, thefiltrate is evaporated down and the residue is combined with 30 mL ethylacetate. After fresh filtration and distilling off the solvent the crudeproduct is crystallised from a little methanol.

Yield: 1.00 g (19%); mass spectroscopy [M+H]⁺=326; meltingrange=148–150° C.

c)6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-2,2-dimethyl-benzo[1,4]oxazin-3-one

50.12 g (154 mmol)8-acetyl-6-benzyloxy-2,2-dimethyl-benzo[1,4]oxazin-3-one are reactedwith selenium dioxide as oxidising agent and activated charcoal inrefluxing dioxane and some water. After cooling, the solid is filteredoff and washed with dioxane. The filtrate is evaporated down and theresidue is dissolved in 550 mL ethanol and refluxed for 30 minutes. Itis filtered and the mother liquor is cooled to −18° C., during whichtime a solid is precipitated which is suction filtered. Afterrecrystallisation from ethanol the product is obtained in the form of abeige solid. Yield: 8.95 g (15%).

d)1-{3-[2-(6-benzyloxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxy-ethylamino]-3-methyl-butyl}-4,4-diethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

Prepared from 406 mg (1 mmol)6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-2,2-dimethyl-benzo[1,4]oxazin-3-oneand 290 mg (1 mmol)1-(3-amino-3-methyl-butyl)-4,4-diethyl-1,4-dihydro-benzo[1,3]oxazin-2-oneanalogously to the method described for Example 5b). The target compoundis purified by chromatography with silica gel on a short column(dichloromethane/methanol gradient). White solid.

Yield: 145 mg (24%); mass spectroscopy [M+H]⁺=616.

e)4,4-diethyl-1-{3-[2-hydroxy-2-(6-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one

130 mg (0.21 mmol)1-{3-[2-(6-benzyloxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxy-ethylamino]-3-methyl-butyl}-4,4-diethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-oneare dissolved in 5 mL methanol and hydrogenated in the presence ofpalladium on charcoal (10%) at ambient temperature. The catalyst issuction filtered, the filtrate is evaporated down and the residue ispurified by chromatography (Reverse phase; acetonitrile/water gradient).White solid.

Yield: 41 mg (37%); mass spectroscopy [M+H]⁺=526.

EXAMPLE 104,4-diethyl-1-{3-[2-hydroxy-2-(5-hydroxy-2-oxo-2,3-dihydro-benzooxazol-7-yl)-ethylamino]-3-methyl-butyl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one

a) 7-acetyl-5-benzyloxy-3H-benzooxazol-2-one

51.1 mL (97.04 mmol) of a phosgene solution (20% by weight in toluene)are added at 0° C. to a solution of 22.7 g (88.22 mmol)1-(3-amino-5-benzyloxy-2-hydroxy-phenyl)-ethanone in toluene (200 mL).Then 30.7 mL (220.6 mmol) triethylamine are added dropwise such that thetemperature does not exceed 5° C. After 1 h stirring at ambienttemperature a further 4.6 mL phosgene solution and 12 mL triethylamineare added at 0 ° C. The mixture is stirred for 1 h at ambienttemperature, diluted with dichloromethane and combined with saturatedaqueous ammonium chloride solution (500 mL) and 2 N aqueous hydrochloricacid (10 mL). After the aqueous phase has been separated off it isexhaustively extracted with dichloromethane. The combined organic phasesare washed with water and saturated aqueous sodium chloride solution,dried with sodium sulphate and evaporated down i. vac., during whichtime a beige solid is precipitated. The precipitate is filtered off,washed with a little toluene and dried at 50° C. i. vac.

Yield: 18.5 g (74%); R_(f)=0.19 (silica gel, toluene/acetone 95:10);ESI-MS: [M+H]⁺=284.

b) 5-benzyloxy-7-(2-ethoxy-2-hydroxy-acetyl)-3H-benzooxazol-2-one

14.4 mL (127.1 mmol) HBr (48% in water) are added to a solution of 12.0g (42.4 mmol) 7-acetyl-5-benzyloxy-3H-benzooxazol-2-one in DMSO (60 mL).The mixture is stirred for 6 h at 60 ° C. under a gentle nitrogencurrent, poured onto 600 mL ice water and stirred for 20 min. Theprecipitate formed is filtered off and washed with ice water and coldwater/ethyl acetate solution (1:1). The precipitate is dissolved in 300mL ethanol and 100 mL ethyl acetate and evaporated down i. vac. Theprocess is repeated with 500 mL toluene and then with 500 mL ethanol.The residue is then dissolved in 250 mL ethanol and refluxed for 1 h.After 30 mL ethanol have been distilled off the mixture is cooled toambient temperature and then to 0° C. The precipitate formed is filteredoff, washed with 80 mL ice-cold ethanol and 200 mL ether and dried at 50° C. i. vac.

Yield: 6.5 g (45%); R_(f)=0.23 (silica gel, dichloromethane/MeOH 25:2);ESI-MS: [M+H—CO₂Et]⁺=270.

c)1-{3-[2-(5-benzyloxy-2-oxo-2,3-dihydro-benzooxazol-7-yl)-2-hydroxy-ethylamino]-3-methyl-butyl}-4,4-diethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

Obtained from 343 mg (1 mmol)5-benzyloxy-7-(2-ethoxy-2-hydroxy-acetyl)-3H-benzooxazol-2-one and 290mg (1 mmol)1-(3-amino-3-methyl-butyl)-4,4-diethyl-1,4-dihydro-benzo[1,3]oxazin-2-oneaccording to the method described for Example 5b). White solid. Yield:160 mg (28%); mass spectroscopy [M−H]⁺=572.

d)4,4-diethyl-1-{3-[2-hydroxy-2-(5-hydroxy-2-oxo-2,3-dihydro-benzooxazol-7-yl)-ethylamino]-3-methyl-butyl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one

150 mg (0.26 mmol)1-{3-[2-(5-benzyloxy-2-oxo-2,3-dihydro-benzooxazol-7-yl)-2-hydroxy-ethylamino]-3-methyl-butyl}-4,4-diethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-oneare dissolved in 5 mL methanol and hydrogenated with palladium oncharcoal as catalyst for 3 hours at ambient temperature. The catalyst isseparated off and the filtrate is evaporated down. Beige solid. Yield:116 mg (92%); mass spectroscopy [M−H]⁺=484.

HPLC method (method A): Symmetry C18 (Waters); 3.5 μm; 4.6×150 mm;Column temperature: 20° C.; gradient acetonitrile/phosphate buffer (pH7) 20:80→80:20 in 30 min., flow: 1.0 mL/min; detection at 220 and 254nm.

EXAMPLE 11 4,4-diethyl-1-{3-[2-hydroxy-2-(7-hydroxy-2-oxo-12-dihydro-quinolin-5-yl)-ethylamino]-3-methyl-butyl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one

a) 2-acetyl-4-benzyloxy-6-nitro-phenyl trifluoromethanesulphonate

Triethylamine (92.7 mL, 0.660 mol) is added to a solution of1-(5-benzyloxy-2-hydroxy-3-nitro-phenyl)-ethanone (90.0 g, 0.313 mol) inabs. dichloromethane (940 mL) at −10 ° C. within 10 min. A solution oftrifluoromethanesulphonic anhydride (65 mL, 0.394 mol) in abs.dichloromethane (40 mL) is added to this red solution within 15 min. andthe resulting mixture is stirred for a further 5 min. at −5° C. Thebrown solution is washed with saturated aqueous ammonium chloride(400mL) and saturated aqueous NaCl (400mL) and the phases are separated.Drying with sodium sulphate and evaporation i. vac. yields the crudeproduct as an oil which becomes solid when left to stand. The crudeproduct is dissolved in ether (150 mL), the solution is combined withhexane (800 mL) and the precipitate formed is filtered off. The solid isstirred with ether/hexane (80/20, 100 mL), filtered off and dried in theoven at 40° C. Yield: 118 g (90%); ESI-MS: [M+H]⁺=420.

b) methyl 3-(2-acetyl-4-benzyloxy-6-nitrophenyl)-acrylate

100 g of molecular sieve (4 Å), tris(dibenzylideneacetone)dipalladium(5.88 g, 6.42 mmol), tri-tert-butylphosphonium-tetrafluoroborate (3.50g, 12.06 mmol), dicyclohexylmethylamine (81.2 mL, 0.371 mol), driedtetrabutylammonium iodide (105.8 g, 0.286 mol) and methyl acrylate (32.6mL, 0.362 mol) are added to a solution of2-acetyl-4-benzyloxy-6-nitro-phenyl trifluoromethanesulphonate (100.0 g,0.238 mol) in dioxane (360 mL) under a nitrogen atmosphere. The reactionmixture is stirred for 2 hours at 80° C., diluted with ether (2 L) andcombined with 500 g silica gel. The suspension is stirred for 10 min.,filtered and the silica gel is washed several times with ether (4×600mL). The combined organic phases are washed with 1 M aqueoushydrochloric acid (300 mL), sodium bicarbonate solution and sodiumchloride solution, dried with sodium sulphate and evaporated down. Theoily crude product is recrystallised from hot ethanol (0.75 L). Theprecipitate is filtered off, washed with ethanol (2×50 mL) and dried at40 ° C.

Yield: 32.2 g (38%); mass spectroscopy: [M+H]⁺=356.

c) 5-acetyl-7-benzyloxy-3,4-dihydro-1H-quinolin-2-one

A suspension of methyl 3-(2-acetyl-4-benzyloxy-6-nitrophenyl)-acrylate(5.0 g, 14.07 mmol) in ethanol (100 mL) is hydrogenated with Raneynickel (3 g) at ambient temperature and 4 bar hydrogen pressure. After 6hours more Raney nickel (2 g) is added and the mixture is hydrogenatedfor a further 2 hours. The catalyst is separated off and the filtrate iscombined with 2 M aqueous hydrochloric acid (15 mL). The product thatcrystallises out is filtered off and dried.

Yield: 1.0 g (24%); mass spectroscopy: [M+H]⁺=296.

d) 5-acetyl-7-benzyloxy-1H-quinolin-2-one

DDQ (15.0 g, 66.08 mmol) is added to a suspension of5-acetyl-7-benzyloxy-3,4-dihydro-1H-quinolin-2-one (13.0 g, 44.02 mmol)in dioxane (130 mL) and the mixture is refluxed for 30 minutes. Thereaction mixture is cooled to ambient temperature and stirred for afurther 2 hours. The precipitate formed is filtered off, washed withdioxane (2×20 mL) and dissolved in dichloromethane/methanol (9:1, 600mL). The organic phase is washed with sodium bicarbonate solution (2×100mL), dried with sodium sulphate and evaporated down. The residue isstirred with methanol, the precipitate formed is filtered off and dried.Yield: 8.3 g (64%); mass spectroscopy: [M+H]⁺=294.

e) 7-benzyloxy-5-(2-chloroacetyl)-1H-quinolin-2-one

5-acetyl-7-benzyloxy-1H-quinolin-2-one (7.0 g, 23.86 mmol) is dissolvedin a mixture of 1,2-dichloroethane (147 mL), glacial acetic acid (43 mL)and water (7 mL) and combined withN-benzyl-trimethylammonium-dichloriodate (19.0 g, 54.58 mmol). Themixture is stirred for 4.5 hours at 65° C., then diluted with sodiumbicarbonate solution and 5% sodium bisulphite solution and stirred for 5minutes. The precipitate formed is filtered off, washed with water (2×20mL) and dried in the oven. Yield: 6.0 g (77%); mass spectroscopy:[M+H]⁺=328.

f) 7-benzyloxy-5-oxiranyl-1H-quinolin-2-one

Lithium borohydride (434 mg, 19.93 mmol) is added to a suspension of7-benzyloxy-5-(2-chloroacetyl)-1H-quinolin-2-one (6 g, 18.31 mmol) inTHF (150 mL) at 0–5 ° C. and the mixture is stirred for 30 minutes. 2.5N sodium hydroxide solution (43 mL, 107.50 mmol) is added and themixture is stirred for 2 hours at 5–10 ° C. and for 2.5 hours at ambienttemperature. Then the reaction mixture is slowly combined with glacialacetic acid (6.5 mL) followed by semi-saturated sodium chloride solution(100 mL) and stirred for a further 5 minutes. The precipitate formed isfiltered off and the aqueous phase is extracted with ethyl acetate/THF(1/1.5×100 mL). The solid filtered off and the organic phases arecombined, dried with sodium sulphate and evaporated down. The crudeproduct is stirred with methanol (30 mL) and the precipitate is filteredoff and dried at ambient temperature. Yield: 4.8 g (89%); massspectroscopy: [M+H]⁺=294.

g)1-{1,3-[2-(7-benzyloxy-2-oxo-1,2-dihydro-quinolin-5-yl)-2-hydroxy-ethylamino]-3-methyl-butyl}-4,4-diethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

A suspension of 7-benzyloxy-5-oxiranyl-1H-quinolin-2-one (112 mg, 0.382mmol) and1-(3-amino-3-methyl-butyl)-4,4-diethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one(220 mg, 0.758 mmol) in isopropanol (1.0 mL) is heated in the microwavefor 1 h to 135 ° C. The mixture is diluted with EtOAc (10 mL) and washedwith 0.5 M aqueous tartaric acid solution, whereupon half the product isprecipitated. The phases are separated and the aqueous suspension iscombined with MeOH until a clear solution is obtained again. The aqueousphase is extracted with dichloromethane and the combined org. phases aredried with sodium sulphate and evaporated down i. vac. The residue isstirred with EtOAc and the precipitate is filtered off and dried i. vac.

Yield: 152 mg (68%); HPLC-MS: R_(t)=14.8 min. (method A).

h)4,4-diethyl-1-{3-[2-hydroxy-2-(7-hydroxy-2-oxo-1,2-dihydro-quinolin-5-yl)-ethylamino]-3-methyl-butyl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one

A suspension of1-{3-[2-(7-benzyloxy-2-oxo-1,2-dihydro-quinolin-5-yl)-2-hydroxy-ethylamino]-3-methyl-butyl}-4,4-diethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one(152 mg, 0.338 mmol) and Pd/C (10%) (40 mg) in MeOH (12 mL) ishydrogenated at RT and 1 bar hydrogen pressure for 4 h. The catalyst isfiltered off through Celite and washed with MeOH (5 mL). The org. phaseis evaporated down, the residue is triturated with EtOAc and theprecipitate formed is filtered off and dried. i. vac.

Yield: 76 mg (46%); R_(f)=0.3 (silica gel,dichloromethane/MeOH/saturated. aqueous ammonia 90:10:0.5); ESI-MS:[M+H]⁺=494.

Specific starting compounds are needed for the examples of synthesisthat follow. Their preparation is described hereinafter.

Intermediate Product 1:1-(3-amino-3-methyl-butyl)-4,4-dilpropyl-1,4-dihydro-benzo[d][1,3]oxazin-2-onehydrochloride

a) 4-(2-amino-phenyl)-heptan-4-ol

90.0 mL (180.00 mmol) of propylmagnesium chloride (2 M in ether) areadded dropwise within 30 min. to a solution of 7.00 mL (54.04 mmol)methyl anthranilate in abs. THF (70 mL) at 0° C. The mixture is stirredfor 1 h at RT and then combined with 100 mL 3 M aqueous ammoniumchloride solution and EtOAc. The phases are separated and the aqueousphase is exhaustively extracted with EtOAc. The combined org. phases arewashed with aqueous KHCO₃ and sat. aqueous NaCl and dried with sodiumsulphate. The crude product is used in the next reaction step withoutany further purification.

Yield: 6.70 g (60%).

b) tert-butyl{3-[2-(1-hydroxy-1-propyl-butyl)-phenylamino]-1,1-dimethyl-propyl}-carbamate

1.40 g (22.27 mmol) sodium cyanoborohydride are added to a solution of3.10 g (14.05 mmol) 4-(2-amino-phenyl)-heptan-4-ol and 3.60 g (17.88mmol) tert-butyl (1,1-dimethyl-3-oxo-propyl)-carbamate in MeOH (40 mL)and AcOH (6 mL). The mixture is stirred for 16 h at RT, diluted withEtOAc and washed with 0.5 M aqueous KHSO₄ and saturated. aqueous NaCl ,dried with sodium sulphate and evaporated down i. vac. The crude productis used in the next reaction step without any further purification.

Yield: 6.00 g (quantitative yield).

c) tert-butyl[1,1-dimethyl-3-(2-oxo-4,4-dipropyl-4H-benzo[d][1,3]oxazin-1-yl)-propyl]-carbamate

8.85 mL (16.81 mmol) phosgene solution (20 wt. % in toluene) are slowlyadded dropwise at 0° C. to a solution of 6.00 g (15.28 mmol)tert-butyl{3-[2-(1-hydroxy-1-propyl-butyl)-phenylamino]-1,1-dimethyl-propyl}-carbamateand 5.32 mL (38.21 mmol) triethylamine in abs. THF (80 mL). The mixtureis stirred for 2 h at RT, diluted with EtOAc, combined with ice and madebasic with sat. aqueous ammonia solution. The aqueous phase isexhaustively extracted with EtOAc and the combined org. phases arewashed with saturated aqueous NaCl, dried with sodium sulphate andevaporated down i. vac. After column chromatography (silica gel,cyclohexane/EtOAc 6:1) the product is obtained as a yellow oil. Yield:4.57 g (71%).

d)1-(3-amino-3-methyl-butyl)-4,4-dipropyl-1,4-dihydro-benzo[d][1,3]oxazin-2-onehydrochloride

A solution of 4.20 g (10.03 mmol) tert-butyl[1,1-dimethyl-3-(2-oxo-4,4-dipropyl-4H-benzo[d][1,3]oxazin-1-yl)-propyl]-carbamatein 35 mL formic acid is stirred for 24 h at RT and then poured onto ice.The aqueous phase is made basic with sat. aqueous ammonia solution andexhaustively extracted with EtOAc. The combined org. extracts are washedwith sat. aqueous NaCl , dried with sodium sulphate and evaporated downi. vac. The residue is taken up in EtOAc (50 mL) and combined with 4 mLHCI solution (sat. in EtOAc). The solution is concentrated byevaporation and twice combined with a little EtOH and evaporated down i.vac. Trituration of the residue with diisopropylether yields the productas a hygroscopic hydrochloride salt. Yield: 2.60 g (73%).

Intermediate Product 2:1-(3-amino-3-methyl-butyl)-4,4-diethyl-7-fluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-one

a) 3-(2-amino-4-fluoro-phenyl)-pentan-3-ol

The product is obtained analogously to intermediate product 1a byreacting methyl 2-amino-4-fluoro-benzoate and ethylmagnesium bromide indichloromethane at −78 ° C.→RT. Yield: 4.1 g (99%).

b)tert-butyl{3-[2-(1-ethyl-1-hydroxy-propyl)-5-fluoro-phenylamino]-1,1-dimethyl-propyl}-carbamate

The product is obtained analogously to intermediate product 1b startingfrom 3-(2-amino-4-fluoro-phenyl)-pentan-3-ol and tert-butyl(1,1-dimethyl-3-oxo-propyl)-carbamate. The crude product is purified bycolumn chromatography (silica gel, dichloromethane/MeOH 100:0→98:2).Yield: 7.70 g (99%).

c) tert-butyl[3-(4,4-diethyl-7-fluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1-dimethyl-propyl]-carbamate

The product is obtained analogously to intermediate product 1c startingfrom tert-butyl{3-[2-(1-ethyl-1-hydroxy-propyl)-5-fluoro-phenylamino]-1,1-dimethyl-propyl}-carbamate.Yield: 4.20 g (51%).

d)1-(3-amino-3-methyl-butyl)-4,4-diethyl-7-fluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-one

The product is obtained analogously to intermediate product 1d startingfrom tert-butyl[3-(4,4-diethyl-7-fluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1-dimethyl-propyl]-carbamateas the free base. Yield: 2.90 g (96%); ESI-MS: [M+H]⁺=309.

Intermediate Product 3:1-(3-amino-3-methyl-butyl)-4,4-diethyl-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one

a) 3-(2-amino-3-methoxy-phenyl)-pentan-3-ol

The product is obtained analogously to intermediate product 1a byreacting methyl 2-amino-3-methoxy-benzoate and ethylmagnesium bromide indichloromethane at −78 ° C. →RT.

Yield: 5.20 g (92%); HPLC-MS: R_(t)=12.85 min. (method A); ESI-MS:[M+H]⁺=210.

b) tert-butyl{3-[2-(1-ethyl-1-hydroxy-propyl)-6-methoxy-phenylamino]-1,1-dimethyl-propyl}-carbamate

The product is obtained analogously to intermediate product 1b startingfrom 3-(2-amino-3-methoxy-phenyl)-pentan-3-ol and tert-butyl(1,1-dimethyl-3-oxo-propyl)-carbamate. The crude product is purified bycolumn chromatography (silica gel, cyclohexane/EtOAc 4:1). Yield: 4.60 g(47%).

c) tert-butyl[3-(4,4-diethyl-8-methoxy-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1-dimethyl-propyl]-carbamate

The product is obtained analogously to intermediate product 1c startingfrom tert-butyl{3-[2-(1-ethyl-1-hydroxy-propyl)-6-methoxy-phenylamino]-1,1-dimethyl-propyl}-carbamate.Yield: 4.60 g (94%).

d) 1-(3-amino-3-methyl-butyl)-4,4-diethyl-8-methoxy-14-dihydro-benzo[d][1,3]oxazin-2-one

The product is prepared as the free base analogously to intermediateproduct 1d starting from tert-butyl[3-(4,4-diethyl-8-methoxy-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1-dimethyl-propyl]-carbamate.Yield: 3.00 g (93%); ESI-MS: [M+H]⁺=321.

Intermediate Product 4:1-(3-amino-3-methyl-butyl)-spiro(cyclohexane-1,4′-2H-3′1′-benzoxazin)-2′-one

a) 1-(2-nitro-phenyl)-cyclohexanol

40.16 mL (80.32 mmol) phenylmagnesium chloride (2 M in THF) are addeddropwise at −50° C. to a solution of 20.0 g (80.32 mmol)2-nitro-iodobenzene in abs. THF (150 mL) under a nitrogen atmosphere.After stirring for 15 min. 9.98 mL (96.30 mmol) cyclohexanone are addedquickly. The mixture is heated to RT and stirred for a further 2 h. Sat.aqueous ammonium chloride solution is added and the aqueous phase isexhaustively extracted with EtOAc. The combined org. extracts are washedwith sat. aqueous NaCl solution, dried with sodium sulphate andevaporated down in vacuo. After column chromatography (silica gel,hexane/EtOAc 20:1) the product is obtained as a brownish oil. Yield:5.20 g (29%); R_(f)=0.26 (silica gel, hexane/EtOAc 10:1); ESI-MS:[M+H—H₂O]⁺=204.

b) 1-(2-amino-phenyl)-cyclohexanol

A suspension of 5.20 g (16.45 mmol) 1-(2-nitro-phenyl)-cyclohexanol and500 mg Raney nickel in EtOH (70 mL) is hydrogenated at RT and under 3bar hydrogen pressure for 4 h. The catalyst is filtered off throughCelite and the filtrate is evaporated down in vacuo. The residue isrecrystallised from hexane. Yield: 1.53 g (49%); R_(f)=0.38 (silica gel,hexane/EtOAc 4:1); ESI-MS: [M+H—H₂O]⁺=174.

c) tert-butyl{3-[2-(1-hydroxy-cyclohexyl)-phenylamino]-1,1-dimethyl-propyl}-carbamate

The product is prepared analogously to intermediate product 1b startingfrom 1-(2-amino-phenyl)-cyclohexanol and tert-butyl(1,1-dimethyl-3-oxo-propyl)-carbamate. After column chromatography(silica gel, hexane/EtOAc 7:1) the product is obtained as a colourlessoil. Yield: 2.65 g (66%); R_(f)=0.50 (silica gel, hexane/EtOAc 4:1).

d) tert-butyl[3-(spiro(cyclohexane-1,4′-2H-3′1′-benzoxazin)-2′-oxo-1-yl)-1,1-dimethyl-propyl]-carbamate

The product is prepared analogously to intermediate product 1c startingfrom tert-butyl{3-[2-(1-hydroxy-cyclohexyl)-phenylamino]-1,1-dimethyl-propyl}-carbamate.

Yield: 2.60 g (92%); R_(f)=0.38 (silica gel, hexane/EtOAc 4:1).

e)1-(3-amino-3-methyl-butyl)-spiro(cyclohexane-1,4′-2H-3′1′-benzoxazin)-2′-one

The product is prepared analogously to intermediate product 1 d startingfrom tert-butyl [3-(spiro(cyclohexane-1,4′-2H-3′,1′-benzoxazin)-2′-oxo-1-yl)-1,1-dimethyl-propyl]-carbamate. Yield: 1.80 g (92%);R_(f)=0.10 (silica gel, dichloromethane/MeOH/sat. aqueous ammonia95:5:0.5); ESI-MS: [M+H]⁺=303.

EXAMPLE 121-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-4,4-dipropyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

a)1-{3-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxy-ethylamino]-3-methyl-butyl}-4,4-dipropyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

86 μL (0.619 mmol) triethylamine are added to a solution of 200 mg(0.564 mmol)1-(3-amino-3-methyl-butyl)-4,4-dipropyl-1,4-dihydro-benzo[d][1,3]oxazin-2-onehydrochloride in abs. THF (5 mL) at RT under a nitrogen atmosphere andthe mixture is stirred for 30 min. 200 mg (0.560 mmol)6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one areadded and the mixture is stirred for another 2 h at RT. The mixture iscooled to 10° C., combined with 51 mg (2.34 mmol) lithium borohydride,heated to RT and stirred for 1 h at RT. It is again cooled to 10° C. andslowly combined with 15 mL water and 20 mL dichloromethane. The phasesare separated and the aqueous phase is extracted with dichloromethane.The combined org. phases are dried with sodium sulphate and evaporateddown in vacuo. The residue is dissolved in EtOAc (8 mL) and acidified topH 2 by the addition of HCl solution (sat. in EtOAc). The precipitateformed is filtered off, washed with EtOAc and dried in vacuo.

Yield: 270 mg (74%; hydrochloride), HPLC-MS: R_(t)=18.7 min. (method A).

b)1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-4,4-dipropyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

A suspension of 270 mg (0.438 mmol)1-{3-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxy-ethylamino]-3-methyl-butyl}-4,4-dipropyl-1,4-dihydro-benzo[d][1,3]oxazin-2-oneand 27 mg Pd/C (10%) in MeOH (8 mL) is hydrogenated at RT and 1 barhydrogen pressure for 3 h. The catalyst is filtered off through Celiteand washed with MeOH (5 mL) and the filtrate is concentrated byevaporation in vacuo. The residue is dissolved in EtOAc/dichloromethane(1:1, 10 mL), acidified to pH 2 by the addition of HCl solution (sat. inEtOAc) and concentrated by evaporation in vacuo. The residue istriturated with ether, filtered and dried in vacuo.

Yield: 80 mg (33%; hydrochloride), HPLC-MS: R_(t)=12.8 min. (method A),ESI-MS: [M+H]⁺=526.

EXAMPLE 13 1-{3-[2-hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,44]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-4,4-dipropyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

a)1-{3-[2-(5-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxy-ethylamino]-3-methyl-butyl}-4,4-dipropyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

The product is prepared analogously to Example 12a starting from5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and1-(3-amino-3-methyl-butyl)-4,4-dipropyl-1,4-dihydro-benzo[d][1,3]oxazin-2-onehydrochloride. The crude product is dissolved in EtOAc, washed with 5%aqueous NaOH solution and purified by column chromatography (silica gel,dichloromethane/MeOH 98:2→90:10).

Yield: 170 mg (49%); HPLC-MS: R_(t)=18.9 min. (method A).

b)1-{3-[2-hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-4,4-dipropyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

The product is prepared analogously to Example 12b starting from1-{3-[2-(5-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxy-ethylamino]-3-methyl-butyl}-4,4-dipropyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one.Yield: 30 mg (19%, hydrochloride); HPLC-MS: R_(t)=13.0 min. (method A);ESI-MS: [M+H]⁺=526.

EXAMPLE 144,4-diethyl-7-fluoro-1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one

a)1-{3-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxy-ethylamino]-3-methyl-butyl}-4,4-diethyl-7-fluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-one

A solution of 232 mg (0.649 mmol)6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and200 mg (0.649 mmol)1-(3-amino-3-methyl-butyl)-4,4-diethyl-7-fluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-onein abs. THF (5 mL) is stirred for 2.5 h at RT. The mixture is cooled to5° C., combined with 60 mg (2.755 mmol) lithium borohydride, heated toRT and stirred for 1 h. The mixture is again cooled to 5° C. and slowlydiluted with 15 ml water and 20 mL dichloromethane. The phases areseparated and the aqueous phase is extracted with dichloromethane. Thecombined org. phases are dried with sodium sulphate and concentrated byevaporation in vacuo. The residue is purified by column chromatography(silica gel, dichloromethane/MeOH 95:5).

Yield: 257 mg (65%); HPLC-MS: R_(t)=16.5 min. (method A).

b)4,4-diethyl-7-fluoro-1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one

The product is prepared analogously to Example 12b starting from1-{3-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxy-ethylamino]-3-methyl-butyl}-4,4-diethyl-7-fluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-one.Yield: 170 mg (78%; hydrochloride); HPLC-MS: R_(t)=10.6 min. (method A);ESI-MS: [M+H]⁺=516.

EXAMPLE 154,4-diethyl-1-{3-[2-hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one

a)1-{3-[2-(5-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxy-ethylamino]-3-methyl-butyl}-4,4-diethyl-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one

The product is prepared analogously to Example 14a starting from5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and1-(3-amino-3-methyl-butyl)-4,4-diethyl-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one.The crude product is purified by column chromatography (silica gel,dichloromethane/MeOH 95:5).

Yield: 70 mg (18%); HPLC-MS: R_(t)=16.5 min. (method A).

b)4,4-diethyl-1-{3-[2-hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one

The product is obtained analogously to Example 12b starting from1-{3-[2-(5-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxy-ethylamino]-3-methyl-butyl}-4,4-diethyl-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one.

Yield: 40 mg (62%); HPLC-MS: R_(t)=13.3 min. (method A); ESI-MS:[M+H]⁺=528.

EXAMPLE 161-(2-{1-[2-hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-cyclopropyl}-ethyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

a) 3-(4,4-dimethyl-2-oxo-4H-benzo[d][1,3oxazin-1-yl]-propionitrile

10.2 mL (123 mmol) bromopropionitrile are added dropwise to a solutionof 20.0 g (112 mmol) 4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-oneand 17.4 g (126 mmol) potassium carbonate in 250 mL acetonitrile and themixture is refluxed overnight. Another 4 mL (48 mmol) ofbromopropionitrile are added and the mixture is refluxed for another 2hours. The solid is suction filtered, the filtrate is evaporated downand the residue is recrystallised from diisopropylether. White solid.

Yield: 22.8 g (88%); mass spectroscopy: [M+H]⁺=231.

b)1-[2-(1-amino-cyclopropyl)-ethyl-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

A suspension of 6.0 g (26 mmol)3-(4,4-dimethyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl]-propionitrile in 120mL diethyl ether is combined with 16.5 mL (56 mmol) titaniumtetra-isopropoxide while being cooled with an ice bath. Then 18.5 mL ofa 3 molar solution of ethylmagnesium bromide in diethyl ether are addeddropwise such that the temperature does not climb past 20° C. Themixture is stirred for 30 minutes at ambient temperature and 7.0 mL (55mmol) boron trifluoride-diethyl ether are added batchwise while coolingwith an ice bath. The mixture is stirred for one hour at ambienttemperature and 150 mL 1 molar sodium hydroxide solution are addeddropwise while cooling. The reaction mixture is diluted with diethylether and the phases are separated. The aqueous phase is extracted withdiethyl ether and the combined organic phases are extracted with sodiumsulphite solution and repeatedly extracted with 1 molar hydrochloricacid. The hydrochloric acid phases are combined, extracted with diethylether, made alkaline with sodium hydroxide solution and exhaustivelyextracted with dichloromethane. The dichloromethane phases are driedwith sodium sulphate and evaporated down. Light yellow oil.

Yield: 1.5 g (22%); mass spectroscopy: [M+H]⁺=261.

c)1-(2-{1-[2-(5-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxy-ethylamino]-cyclopropyl}-ethyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

900 mg (2.5 mmol)5-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and700 mg (2.7 mmol)1-[2-(1-amino-cyclopropyl)-ethyl]-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-oneare dissolved in 20 mL ethanol and stirred in each case for 30 minutesat 80° C. and 50° C. The reaction mixture is cooled, combined with 200mg (5.3 mmol) sodium borohydride and stirred for 2 hours at ambienttemperature. Glacial acetic acid is added, the mixture is stirred for 10minutes and evaporated down. The residue is taken up in dichloromethaneand washed successively with potassium hydrogen sulphate solution, 15%potassium carbonate solution and sodium hydrogen carbonate solution.Then the organic phase is dried with sodium sulphate and freed fromsolvent. The residue is purified by column chromatography (silica gel;ethyl acetate/methanol/ammonia gradient). Recrystallisation fromdiisopropylether. White solid.

Yield: 690 mg (49%); mass spectroscopy: [M+H]⁺=558.

d)1-(2-{1-[2-hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-cyclopropyl}-ethyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

650 mg (1.17 mmol)1-(2-{1-[2-(5-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxy-ethylamino]-cyclopropyl}-ethyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-oneare dissolved in 30 mL methanol, combined with palladium on charcoal(10%) and hydrogenated at ambient temperature and 3 bar hydrogenpressure.

Yield: 240 mg (44%); mass spectroscopy: [M+H]⁺=468.

EXAMPLE 171-(2-{1-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-cyclopropyl}-ethyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

a) 1-(2-{1-[2-(6-benzyloxy-3-oxo-34-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxy-ethylamino]-cyclopropyl}-ethyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

Prepared from 900 mg (2.5 mmol)6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and700 mg (2.7 mmol)1-[2-(1-amino-cyclopropyl)-ethyl]-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-oneanalogously to the method described for Example 16a. White solid. Yield:630 mg (45%); mass spectroscopy: [M+H]⁺=558.

b)1-(2-{1-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-cyclopropyl}-ethyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-ol590 mg (1.06 mmol)1-(2-{1-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxy-ethylamino]-cyclopropyl}-ethyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-oneare dissolved in 30 mL methanol and hydrogenated in the presence ofpalladium on charcoal (10%) at ambient temperature and 3 bar hydrogenpressure. Yield: 180 mg (36%); mass spectroscopy: [M+H]⁺=468.

The Examples listed below are obtained analogously to the methodsdescribed hereinbefore.

EXAMPLE 181-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-spiro(cyclohexane-1,4′-2H-3′,1′-benzoxazin)-2′-one

EXAMPLE 191-{3-[2-hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-spiro(cyclohexane-1,4′-2H-3′,1′-benzoxazin)-2′-one

EXAMPLE 204,4-dimethyl-1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-propyl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one

EXAMPLE 214,4-dimethyl-1-{3-[2-hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-propyl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one

As has been found, the compounds of general formula 1 are characterisedby their range of uses in the therapeutic field. Particular mentionshould be made of those applications for which the compounds of formula1 according to the invention may preferably be used on the basis oftheir pharmaceutical activity as betamimetics.

These include, for example, the treatment of inflammatory andobstructive respiratory complaints, preferably the treatment of asthmaor COPD (chronic obstructive pulmonary disease), the inhibition ofpremature labour in midwifery (tocolysis), the restoration of the sinusrhythm in the heart in cases of atrio-ventricular block as well as thecorrecting of bradycardic heart rhythm disorders (antiarrhythmic agent),the treatment of circulatory shock (vasodilatation and increasing theheart-time volume) as well as the treatment of itching and skininflammation.

In one aspect the present invention relates to the use of the compoundsof formula 1 as pharmaceutical compositions. In another aspect thepresent invention relates to the use of the compounds of formula 1 forpreparing a pharmaceutical composition for the treatment of diseases,wherein therapeutically effective doses of a betamimetic can deliver atherapeutic benefit. It is particularly preferable to use compounds offormula 1 for preparing a pharmaceutical composition for the treatmentof inflammatory and obstructive respiratory complaints, particularlypreferably the treatment of asthma or COPD, for inhibiting prematurelabour in midwifery (tocolysis), for restoring the sinus rhythm in theheart in cases of atrio-ventricular block, for correcting bradycardicheart rhythm disorders, for treating circulatory shock (vasodilatationand increasing the heart-time volume) and for the treatment of itchingand skin inflammation. It is particularly preferred according to theinvention to use compounds of formula 1 for preparing a pharmaceuticalcomposition for the treatment of inflammatory and obstructiverespiratory complaints, particularly preferably for the treatment ofasthma or COPD. Also of particular importance is the use of compounds offormula 1 as described above for preparing a pharmaceutical compositionfor a once-a-day treatment of inflammatory and obstructive respiratorycomplaints, particularly preferably for a once-a-day treatment of asthmaor COPD.

Suitable preparations for administering the compounds of formula 1include for example tablets, capsules, suppositories, solutions,powders, etc. The content of the pharmaceutically active compound(s)should be in the range from 0.05 to 90 wt. -%, preferably 0.1 to 50 wt.-% of the composition as a whole. Suitable tablets may be obtained, forexample, by mixing the active substance(s) with known excipients, forexample inert diluents such as calcium carbonate, calcium phosphate orlactose, disintegrants such as corn starch or alginic acid, binders suchas starch or gelatine, lubricants such as magnesium stearate or talcand/or agents for delaying release, such as carboxymethyl cellulose,cellulose acetate phthalate, or polyvinyl acetate. The tablets may alsocomprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups or elixirs containing the active substances according to theinvention may additionally contain a sweetener such as saccharine,cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouringsuch as vanillin or orange extract. They may also contain suspensionadjuvants or thickeners such as sodium carboxymethyl cellulose, wettingagents such as, for example, condensation products of fatty alcoholswith ethylene oxide, or preservatives such as p-hydroxybenzoates.

Solutions are prepared in the usual way, e.g. with the addition ofisotonic agents, preservatives such as p-hydroxybenzoates or stabiliserssuch as alkali metal salts of ethylenediaminetetraacetic acid,optionally using emulsifiers and/or dispersants, while if water is usedas diluent, for example, organic solvents may optionally be used assolubilisers or dissolving aids, and the solutions may be transferredinto injection vials or ampoules or infusion bottles.

Capsules containing one or more active substances may for example beprepared by mixing the active substances with inert carriers such aslactose or sorbitol and packing them into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriersprovided for this purpose, such as neutral fats or polyethyleneglycol orthe derivatives thereof.

Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.petroleum fractions), vegetable oils (e.g. groundnut or sesame oil),mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carrierssuch as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk),synthetic mineral powders (e.g. highly dispersed silicic acid andsilicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers(e.g. lignin, spent sulphite liquors, methylcellulose, starch andpolyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc,stearic acid and sodium lauryl sulphate).

For oral use the tablets may obviously contain, in addition to thecarriers specified, additives such as sodium citrate, calcium carbonateand dicalcium phosphate together with various additional substances suchas starch, preferably potato starch, gelatine and the like. Lubricantssuch as magnesium stearate, sodium laurylsulphate and talc may also beused to produce the tablets. In the case of aqueous suspensions theactive substances may be combined with various flavour enhancers orcolourings in addition to the abovementioned excipients.

In the preferred use of the compounds of formula 1 for the treatment ofasthma or COPD according to the invention it is particularly preferredto use preparations or pharmaceutical formulations which are suitablefor inhalation. Inhalable preparations include inhalable powders,propellant-containing metered-dose aerosols or propellant-free inhalablesolutions Within the scope of the present invention, the termpropellant-free inhalable solutions also includes concentrates orsterile ready-to-use inhalable solutions. The formulations which may beused within the scope of the present invention are described in moredetail in the next part of the specification

The inhalable powders which may be used according to the invention maycontain 1either on its own or in admixture with suitable physiologicallyacceptable excipients.

If the active substances 1are present in admixture with physiologicallyacceptable excipients, the following physiologically acceptableexcipients may be used to prepare these inhalable powders according tothe invention: monosaccharides (e.g. glucose or arabinose),disaccharides (e.g. lactose, saccharose, maltose), oligo- andpolysaccharides (e.g. dextrans), polyalcohols (e.g. sorbitol, mannitol,xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures ofthese excipients. Preferably, mono- or disaccharides are used, while theuse of lactose or glucose is preferred, particularly, but notexclusively, in the form of their hydrates. For the purposes of theinvention, lactose is the particularly preferred excipient, whilelactose monohydrate is most particularly preferred.

Within the scope of the inhalable powders according to the invention theexcipients have a maximum average particle size of up to 250 μm,preferably between 10 and 150 μm, most preferably between 15 and 80 μm.In some cases it may seem appropriate to add finer excipient fractionswith an average particle size of 1 to 9 μm to the excipient mentionedabove. These finer excipients are also selected from the group ofpossible excipients listed hereinbefore. Finally, in order to preparethe inhalable powders according to the invention, micronised activesubstance 1, preferably with an average particle size of 0.5 to 10 μm,more preferably from 1 to 5 μm, is added to the excipient mixture.Processes for producing the inhalable powders according to the inventionby grinding and micronising and lastly mixing the ingredients togetherare known from the prior art.

The inhalable powders according to the invention may be administeredusing inhalers known from the prior art.

The inhalation aerosols containing propellant gas according to theinvention may contain the compounds 1dissolved in the propellant gas orin dispersed form. The compounds 1may be contained in separateformulations or in a common formulation, in which the compounds 1areeither both dissolved, both dispersed or in each case only one componentis dissolved and the other is dispersed. The propellant gases which maybe used to prepare the inhalation aerosols are known from the prior art.Suitable propellant gases are selected from among hydrocarbons such asn-propane, n-butane or isobutane and halohydrocarbons such asfluorinated derivatives of methane, ethane, propane, butane,cyclopropane or cyclobutane. The above-mentioned propellant gases may beused on their own or mixed together. Particularly preferred propellantgases are halogenated alkane derivatives selected from TG134a and TG227and mixtures thereof.

The propellant-driven inhalation aerosols may also contain otheringredients such as co-solvents, stabilisers, surfactants, antioxidants,lubricants and pH adjusters. All these ingredients are known in the art.

The propellant-driven inhalation aerosols according to the inventionmentioned above may be administered using inhalers known in the art(MDIs=metered dose inhalers).

Moreover, the active substances 1according to the invention may beadministered in the form of propellant-free inhalable solutions andsuspensions. The solvent used may be an aqueous or alcoholic, preferablyan ethanolic solution. The solvent may be water on its own or a mixtureof water and ethanol. The relative proportion of ethanol compared withwater is not limited but the maximum is preferably up to 70 percent byvolume, more particularly up to 60 percent by volume and most preferablyup to 30 percent by volume. The remainder of the volume is made up ofwater. The solutions or suspensions containing 1are adjusted to a pH of2 to 7, preferably 2 to 5, using suitable acids. The pH may be adjustedusing acids selected from inorganic or organic acids. Examples ofparticularly suitable inorganic acids include hydrochloric acid,hydrobromic acid, nitric acid, sulphuric acid and/or phosphoric acid.Examples of particularly suitable organic acids include ascorbic acid,citric acid, malic acid, tartaric acid, maleic acid, succinic acid,fumaric acid, acetic acid, formic acid and/or propionic acid etc.Preferred inorganic acids are hydrochloric and sulphuric acids. It isalso possible to use the acids which have already formed an acidaddition salt with one of the active substances. Of the organic acids,ascorbic acid, fumaric acid and citric acid are preferred. If desired,mixtures of the above acids may be used, particularly in the case ofacids which have other properties in addition to their acidifyingqualities, e.g. as flavourings, antioxidants or complexing agents, suchas citric acid or ascorbic acid, for example. According to theinvention, it is particularly preferred to use hydrochloric acid toadjust the pH.

If desired, the addition of editic acid (EDTA) or one of the known saltsthereof, sodium edetate, as stabiliser or complexing agent may beomitted in these formulations. Other embodiments may contain thiscompound or these compounds. In a preferred embodiment the content basedon sodium edetate is less than 100 mg/100 ml, preferably less than 50mg/100 ml, more preferably less than 20 mg/100 ml. Generally, inhalablesolutions in which the content of sodium edetate is from 20 to mg/100 mlare preferred.

Co-solvents and/or other excipients may be added to the propellant-freeinhalable solutions. Preferred co-solvents are those which containhydroxyl groups or other polar groups, e.g. alcohols—particularlyisopropyl alcohol, glycols—particularly propyleneglycol,polyethyleneglycol, polypropyleneglycol, glycolether, glycerol,polyoxyethylene alcohols and polyoxyethylene fatty acid esters. Theterms excipients and additives in this context denote anypharmacologically acceptable substance which is not an active substancebut which can be formulated with the active substance or substances inthe physiologically suitable solvent in order to improve the qualitativeproperties of the active substance formulation. Preferably, thesesubstances have no pharmacological effect or, in connection with thedesired therapy, no appreciable or at least no undesirablepharmacological effect. The excipients and additives include, forexample, surfactants such as soya lecithin, oleic acid, sorbitan esters,such as polysorbates, polyvinylpyrrolidone, other stabilisers,complexing agents, antioxidants and/or preservatives which guarantee orprolong the shelf life of the finished pharmaceutical formulation,flavourings, vitamins and/or other additives known in the art. Theadditives also include pharmacologically acceptable salts such as sodiumchloride as isotonic agents.

The preferred excipients include antioxidants such as ascorbic acid, forexample, provided that it has not already been used to adjust the pH,vitamin A, vitamin E, tocopherols and similar vitamins and provitaminsoccurring in the human body.

Preservatives may be used to protect the formulation from contaminationwith pathogens. Suitable preservatives are those which are known in theart, particularly cetyl pyridinium chloride, benzalkonium chloride orbenzoic acid or benzoates such as sodium benzoate in the concentrationknown from the prior art. The preservatives mentioned above arepreferably present in concentrations of up to 50 mg/100 ml, morepreferably between 5 and 20 mg/100 ml.

Preferred formulations contain, in addition to the solvent water and theactive substance 1, only benzalkonium chloride and sodium edetate. Inanother preferred embodiment, no sodium edetate is present.

The dosage of the compounds according to the invention is naturallyhighly dependent on the method of administration and the complaint whichis being treated. When administered by inhalation the compounds offormula 1 are characterised by a high potency even at doses in the μgrange. The compounds of formula 1 may also be used effectively above theμg range. The dosage may then be in the milligram range, for example.

In another aspect the present invention relates to the above-mentionedpharmaceutical formulations as such, which are characterised in thatthey contain a compound of formula 1, particularly preferably theabove-mentioned pharmaceutical formulations administered by inhalation.

The following examples of formulations illustrate the present inventionwithout restricting its scope:

Examples of Pharmaceutical Formulations

A) Tablets per tablet active substance of formula 1 100 mg lactose 140mg maize starch 240 mg polyvinylpyrrolidone  15 mg magnesium stearate  5mg 500 mg

The finely ground active substance, lactose and some of the corn starchare mixed together. The mixture is screened, then moistened with asolution of polyvinylpyrrolidone in water, kneaded, wet-granulated anddried. The granules, the remaining corn starch and the magnesiumstearate are screened and mixed together. The mixture is compressed toproduce tablets of suitable shape and size.

B) Tablets per tablet active substance of formula 1 80 mg lactose 55 mgmaize starch 190 mg  microcrystalline cellulose 35 mgpolyvinylpyrrolidone 15 mg sodium-carboxymethyl starch 23 mg magnesiumstearate  2 mg 400 mg 

The finely ground active substance, some of the corn starch, lactose,microcrystalline cellulose and polyvinylpyrrolidone are mixed together,the mixture is screened and worked with the remaining corn starch andwater to form a granulate which is dried and screened. The sodiumcarboxymethyl starch and the magnesium stearate are added and mixed inand the mixture is compressed to form tablets of a suitable size.

C) Ampoule solution active substance of formula 1 50 mg sodium chloride50 mg water for inj. 5 ml

The active substance is dissolved in water at its own pH or optionallyat pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. Thesolution obtained is filtered free from pyrogens and the filtrate istransferred under aseptic conditions into ampoules which are thensterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50mg of active substance.

D) Metered-dose aerosol active substance of formula 1 0.005 sorbitolantrioleate 0.1  monofluorotrichloromethane and ad 100 TG134a:TG227 2:1

The suspension is transferred into a conventional aerosol container witha metering valve. Preferably, 50 μl of suspension are delivered perspray. The active substance may also be metered in higher doses ifdesired (e.g. 0.02% by weight).

F) Powder for inhalation active substance of formula 1 12 μg lactosemonohydrate ad 10 mg

The powder for inhalation is produced in the usual way by mixing theindividual ingredients together.

1. A compound of formula 1″

wherein: V is —CH₂—, —NH—, or —O—; R^(a) and R^(b) are eachindependently hydrogen, C₁₋₄-alkyl, or halogen-C₁₋₄-alkyl, or R^(a) andR^(b) together are a C₂₋₅-alkylene bridge wherein one or more hydrogenatoms are optionally replaced by halogen; R¹ and R^(1′) are eachindependently hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, halogen-C₁₆-alkyl,halogen-C₃₋₆-cycloalkyl, or C₁₋₆-alkylene-C₃₋₆-cycloalkyl, or R¹ andR^(1′) together are a C₂₋₅-alkylene bridge wherein one or more hydrogenatoms are optionally replaced by halogen; R², R^(2′), R^(2″), andR^(2′″) are each independently hydrogen, C₁₋₆-alkyl,halogen-C₁₋₆-alkylene, OH, HO—C₁₋₆-alkylene, —O—C₁₋₆-alkyl,C₆₋₁₀-aryl,-C₁₋₄-alkylene, C₆₋₁₀-aryl-C₁₋₆-alkylene-O, COOH,COOC₁₋₆-alkyl, O—C₁₋₆-alkylene-COOH, O—C₁₋₆-alkylene-COOC₁₋₆-alkyl,NHSO₂—C₁₋₆-alkyl, CN, NH₂, NH—C₁₋₆-alkyl, N(C₁₋₆-alkyl)₂, NO₂,S—C₁₋₆-alkyl, SO₂—C₁₋₆- alkyl, SO—C ₁₋₆-alkyl, O(CO)C₁₋₆-alkyl,COC₁₋₆-alkyl, NHCOC₁₋₆-alkyl, or halogen; and n is 0, 1, or 2, or anoptical isomer thereof, or a corresponding acid addition salt thereofwith a pharmacologically acceptable acid.
 2. The compound of formula 1″according to claim 1, wherein: V is —CH₂— or —O—; R^(a) and R^(b) areeach independently hydrogen, C₁₋₄-alkyl, or halogen-C₁₋₄-alkyl, or R^(a)and R^(b) together are a C₂₋₅-alkylene bridge wherein one or morehydrogen atoms are optionally replaced by halogen; R¹ and R^(1′) areeach independently hydrogen, methyl, ethyl, propyl, or cyclopropyl, orR¹ and R^(1′) together are —CH₂—CH₂—CH₂—CH₂— or —CH₂CH₂—CH₂—CH₂—CH₂—;R²and R^(2′″) are each hydrogen; and R²and R^(2″) are each independentlyhydrogen, methyl, CF₃, OH, methyloxy, benzyloxy, COOH, COOCH₃, orfluorine, or an optical isomer thereof, or a corresponding acid additionsalt thereof with a pharmacologically acceptable acid.
 3. A compound offormula 1′″

wherein: V is —CH₂—, —NH—, or —O—; R^(a) and R^(b) are eachindependently hydrogen, C₁₋₄-alkyl, or halogen-C₁₋₄-alkyl, or R^(a) andR^(b) together are a C₂₋₅-alkylene bridge wherein one or more hydrogenatoms are optionally replaced by halogen; R¹ and R^(1′) are eachindependently hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, halogen-C₁₋₆-alkyl,halogen-C₃₋₆-cycloalkyl, or C₁₋₆-alkylene-C₃₋₆-cycloalkyl, or R¹ andR^(1′) together are a C₂₋₅-alkylene bridge wherein one or more hydrogenatoms are optionally replaced by halogen; R² , R^(2′), R^(2″) andR^(2′″) are each independently hydrogen, C₁-alkyl,halogen-C₁₋₆-alkylene, OH, HO—C₁₋₆-alkylene, —O—C₁₋₆-alkyl, C₆₋₁₀,-aryl-C₁₋₄-alkylene, C₆₋₁₀-aryl-C₁₋₆-alkylene-O, COOH, COOC₁₋₆-alkyl,O—-C₁₋₆-alkylene-COOH, O—C₁₋₆-alkylene-COOC₁₋₆-alkyl, NHSO₂—C₁₋₆-alkyl,CN, NH₂, NH—C₁₋₆-alkyl, N(C₁₋₆-alkyl)NO₂, S—C₁₋₆-alkyl, SO₂—C₁₋₆-alkyl,O(CO)C₁₋₆-alkyl, COC₁₋₆-alkyl, NHCOC₁₋₆-alkyl, or halogen; and n is 0,1, or 2, or an optical isomer thereof, or a corresponding acid additionsalt thereof with a pharmacologically acceptable acid.
 4. The compoundof formula 1′″ according to claim 3, wherein: V is —CH₂— or —O—; R^(a)and R^(b) are each independently hydrogen, -C₁₋₄-alkyl, or R^(a) andR^(b) together are a C₂₋₅-alkylene- ₁₃ bridge wherein one or morehydrogen atoms are optionally replaced by halogen; R¹ and R_(1′) areeach independently hydrogen, methyl, ethyl, propyl, or cyclopropyl, orR¹ and R^(1′) together are —CH₂—CH₂, —CH₂—CH₂—CH₂—C₂—, or—CH₂—CH²—CH₂—CH₂—CH₂—; R² and R^(2′″) are each hydrogen; and R^(2′) andR2″ are each independently hydrogen, methyl, CF₃, OH, methyloxy,benzyloxy, COOH, COOCH₃, or fluorine, an optical isomer thereof, or thecorresponding acid addition salt thereof with a pharmacologicallyacceptable acid.
 5. A compound of formula 1″″

wherein: V is —CH₂—, NH—, or —O—; R^(a) and R^(b) are each independentlyhydrogen, C₁₋₄-alkyl, or halogen-C₁₋₄-alkyl, or R^(a) and R^(b) togetherare a C₂₋₅-alkylene bridge wherein one or more hydrogen atoms areoptionally replaced by halogen; R₁ and R_(1′) are each independentlyhydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, halogen-C₁₋₆-alkyl,halogen-C₃₋₆-cycloalkyl, or C₁₋₆-alkylene-C₃₋₆-cycloalkyl, or R¹ andR^(1′) together are a C₂₋₅-alkylene bridge wherein one or more hydrogenatoms are optionally replaced by halogen; R², R^(2′), and R^(2′″), areeach independently hydrogen, C₁₋₆alkyl, halogen-C₁₋₆-alkylene, OH,HO—C₁₋₆-alkylene, —O—C₁₋₆-alkyl, c₆₋₁₀-aryl-C₁₋₄-alkylene,C₆₋₁₀-aryl-C₁₋₆-alkylene-O, COOH, COOC₁₋₆-alkyl, O—C₁₋₆-alkylene-COOH,O—C₁₋₆-alkylene-COOC₁₋₆-alkyl, NHSO₂—C₁₋₆-alkyl, CN, NH₂, NH—C₁₋₆-alkyl,N(C₁₋₆-alkyl)₂, NO₂, S—C₁₋₆-alkyl, SO₂—C₁₋₆-alkyl, SO—C₁₋₆-alkyl ,O(CO)C₁₋₆-alkyl, COC₁₋₆-alkyl, NHCOC₁₋₆-alkyl, or halogen; and is 0, 1,or 2, or an optical isomer thereof, or a corresponding acid additionsalt thereof with a pharmacologically acceptable acid thereof.
 6. Thecompound of formula 1″″ according to claim 5, wherein: V is —CH₂—and—O—; R^(a) and R^(b) are each independently hydrogen, C₁₋₄-alkyl, andhalogen-C₁₋₄-alkyl, or R^(a) and R^(b) together are aC₂₋₅-alkylene-_bridge wherein one or more hydrogen atoms are optionallyreplaced by halogen; R¹ and R^(1′) are each independently hydrogen,methyl, ethyl, propyl, cyclopropyl, or R¹ and R^(1′) together are—CH₂—CH₂—CH₂—CH₂— or CH₂—CH₂—CH₂—CH₂—CH₂—; R² and R^(2′″) are eachhydrogen; and R^(2′) and R^(2″) are each independently hydrogen, methyl,CF₃, OH, methyloxy, benzyloxy, COOH, COOCH₃, or fluorine, an opticalisomer thereof, or a corresponding acid addition salt thereof with apharmacologically acceptable acid.
 7. A pharmaceutical compositioncomprising the compound of formula 1″ according to claim 1 and apharmaceutically acceptable carrier or excipient thereof.
 8. Apharmaceutical composition comprising two or more compounds of formula1″ according to claim 1 and a pharmaceutically acceptable carrier orexcipient thereof.
 9. The pharmaceutical composition according to claim7 or claim 8, wherein the pharmaceutical composition is administered byinhalation.
 10. A pharmaceutical composition according to claim 9, whichis in the form of an inhalable powder, propellant-containingmetered-dose aerosol or propellant-free inhalable solution.